This file was created by the TYPO3 extension publications --- Timezone: CEST Creation date: 2022-11-28 Creation time: 06:02:12 --- Number of references 283 article Loft2022 A macrophage-hepatocyte glucocorticoid receptor axis coordinates fasting ketogenesis. Fasting metabolism and immunity are tightly linked; however, it is largely unknown how immune cells contribute to metabolic homeostasis during fasting in healthy subjects. Here, we combined cell-type-resolved genomics and computational approaches to map crosstalk between hepatocytes and liver macrophages during fasting. We identified the glucocorticoid receptor (GR) as a key driver of fasting-induced reprogramming of the macrophage secretome including fasting-suppressed cytokines and showed that lack of macrophage GR impaired induction of ketogenesis during fasting as well as endotoxemia. Mechanistically, macrophage GR suppressed the expression of tumor necrosis factor (TNF) and promoted nuclear translocation of hepatocyte GR to activate a fat oxidation/ketogenesis-related gene program, cooperatively induced by GR and peroxisome proliferator-activated receptor alpha (PPARα) in hepatocytes. Together, our results demonstrate how resident liver macrophages directly influence ketogenesis in hepatocytes, thereby also outlining a strategy by which the immune system can set the metabolic tone during inflammatory disease and infection. 2022 Mar eng Cell metabolism 34
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473-486.e9 fasting, genomics, glucocorticoid receptor, hepatocyte, ketogenesis, liver, macrophage, nuclear receptor, transcripional regulation, tumor necrosis factor Anne Loft Søren Fisker Schmidt Giorgio Caratti Ulrich Stifel Jesper Havelund Revathi Sekar Yun Kwon Alba Sulaj Kan Kau Chow Ana Jimena Alfaro Thomas Schwarzmayr Nikolaj Rittig Mads Svart Foivos-Filippos Tsokanos Adriano Maida Andreas Blutke Annette Feuchtinger Niels Møller Matthias Blüher Peter Nawroth Julia Szendrödi Nils J. Færgeman Anja Zeigerer Jan Tuckermann Stephan Herzig
article Krueger2022 Inhibition of Cdk5 Ameliorates Skeletal Bone Loss in Glucocorticoid-Treated Mice. Glucocorticoids (GCs) are widely used to treat inflammatory diseases. However, their long-term use leads to glucocorticoid-induced osteoporosis, increasing morbidity and mortality. Both anabolic and anti-resorptive drugs are used to counteract GC-induced bone loss, however, they are expensive and/or have major side effects. Therefore, identifying new targets for cost-effective, small-molecule inhibitors is essential. We recently identified cyclin-dependent kinase 5 (Cdk5) as a suppressor of osteoblast differentiation and showed that its inhibition with roscovitine promoted osteoblastogenesis, thus improving the skeletal bone mass and fracture healing. Here, we assessed whether Cdk5 knockdown or inhibition could also reverse the GC-mediated suppression of osteoblast differentiation, bone loss, and fracture healing. We first demonstrated that Cdk5 silencing abolished the dexamethasone (Dex)-induced downregulation of alkaline phosphatase (Alp) activity, osteoblast-specific marker gene expression (Runx2, Sp7, Alpl, and Bglap), and mineralization. Similarly, Cdk5 inhibition rescued Dex-induced suppression of Alp activity. We further demonstrated that Cdk5 inhibition reversed prednisolone (Pred)-induced bone loss in mice, due to reduced osteoclastogenesis rather than improved osteoblastogenesis. Moreover, we revealed that Cdk5 inhibition failed to improve Pred-mediated impaired fracture healing. Taken together, we demonstrated that Cdk5 inhibition with roscovitine ameliorated GC-mediated bone loss but did not reverse GC-induced compromised fracture healing in mice. 2022 Feb eng Biomedicines 10
bone, cyclin-dependent kinase 5, fracture healing, glucocorticoid-induced osteoporosis, glucocorticoids, osteoblasts, osteoclasts, osteocytes, roscovitine Benjamin Thilo Krüger Lena Steppe Sabine Vettorazzi Melanie Haffner-Luntzer Sooyeon Lee Ann-Kristin Dorn Anita Ignatius Jan Tuckermann Mubashir Ahmad
article Caratti2022 The glucocorticoid receptor associates with RAS complexes to inhibit cell proliferation and tumor growth. Mutations that activate members of the RAS family of GTPases are associated with various cancers and drive tumor growth. The glucocorticoid receptor (GR), a member of the nuclear receptor family, has been proposed to interact with and inhibit the activation of components of the PI3K-AKT and MAPK pathways downstream of RAS. In the absence of activating ligands, we found that GR was present in cytoplasmic KRAS-containing complexes and inhibited the activation of wild-type and oncogenic KRAS in mouse embryonic fibroblasts and human lung cancer A549 cells. The DNA binding domain of GR was involved in the interaction with KRAS, but GR-dependent inhibition of RAS activation did not depend on the nuclear translocation of GR. The addition of ligand released GR-dependent inhibition of RAS, AKT, the MAPK p38, and the MAPKK MEK. CRISPR-Cas9-mediated deletion of GR in A549 cells enhanced tumor growth in xenografts in mice. Patient samples of non-small cell lung carcinomas showed lower expression of , the gene encoding GR, compared to adjacent normal tissues and lower expression correlated with a worse disease outcome. These results suggest that glucocorticoids prevent the ability of GR to limit tumor growth by inhibiting RAS activation, which has potential implications for the use of glucocorticoids in patients with cancer. 2022 mar 1937-9145 10.1126/scisignal.abm4452 Science signaling 15 eabm4452 Animals; Cell Proliferation; Fibroblasts, metabolism; Humans; Lung Neoplasms, drug therapy, genetics; Mice; Phosphatidylinositol 3-Kinases, metabolism; Receptors, Glucocorticoid, genetics, metabolism Bozhena Caratti Miray Fidan Giorgio Caratti Kristina Breitenecker Melanie Engler Naser Kazemitash Rebecca Traut Rainer Wittig Emilio Casanova Mohammad Reza Ahmadian Jan P. Tuckermann Herwig P. Moll Ion Cristian Cirstea article Schoppa2022 Osteoblast lineage Sod2 deficiency leads to an osteoporosis-like phenotype in mice. Osteoporosis is a systemic metabolic skeletal disease characterized by low bone mass and strength associated with fragility fractures. Oxidative stress, which results from elevated intracellular reactive oxygen species (ROS) and arises in the aging organism, is considered one of the critical factors contributing to osteoporosis. Mitochondrial (mt)ROS, as the superoxide anion (O2-) generated during mitochondrial respiration, are eliminated in the young organism by antioxidant defense mechanisms, including superoxide dismutase 2 (SOD2), the expression and activity of which are decreased in aging mesenchymal progenitor cells, accompanied by increased mtROS production. Using a mouse model of osteoblast lineage cells with Sod2 deficiency, we observed significant bone loss in trabecular and cortical bones accompanied by decreased osteoblast activity, increased adipocyte accumulation in the bone marrow and augmented osteoclast activity, suggestive of altered mesenchymal progenitor cell differentiation and osteoclastogenesis. Furthermore, osteoblast senescence was increased. To date, there are only a few studies suggesting a causal association between mtROS and cellular senescence in tissue in vivo. Targeting SOD2 to improve redox homeostasis could represent a potential therapeutic strategy for maintaining bone health during aging. 2022 may 1754-8411 10.1242/dmm.049392 Disease models & mechanisms 15 Animals; Mice; Osteoblasts, metabolism; Osteoclasts, metabolism; Osteoporosis, metabolism; Phenotype; Reactive Oxygen Species, metabolism; Superoxide Dismutase, metabolism; Mitochondrial dysfunction; Osteoporosis; Reactive oxygen species; Senescence; Skeletal aging Astrid M. Schoppa Xiangxu Chen Jan-Moritz Ramge Anna Vikman Verena Fischer Melanie Haffner-Luntzer Jana Riegger Jan Tuckermann Karin Scharffetter-Kochanek Anita Ignatius article Ahmad2022 Inhibition of Cdk5 increases osteoblast differentiation and bone mass and improves fracture healing. Identification of regulators of osteoblastogenesis that can be pharmacologically targeted is a major goal in combating osteoporosis, a common disease of the elderly population. Here, unbiased kinome RNAi screening in primary murine osteoblasts identified cyclin-dependent kinase 5 (Cdk5) as a suppressor of osteoblast differentiation in both murine and human preosteoblastic cells. Cdk5 knockdown by siRNA, genetic deletion using the Cre-loxP system, or inhibition with the small molecule roscovitine enhanced osteoblastogenesis in vitro. Roscovitine treatment significantly enhanced bone mass by increasing osteoblastogenesis and improved fracture healing in mice. Mechanistically, downregulation of Cdk5 expression increased Erk phosphorylation, resulting in enhanced osteoblast-specific gene expression. Notably, simultaneous Cdk5 and Erk depletion abrogated the osteoblastogenesis conferred by Cdk5 depletion alone, suggesting that Cdk5 regulates osteoblast differentiation through MAPK pathway modulation. We conclude that Cdk5 is a potential therapeutic target to treat osteoporosis and improve fracture healing. 2022 apr 2095-4700 10.1038/s41413-022-00195-z Bone research 10 33 Mubashir Ahmad Benjamin Thilo Krüger Torsten Kroll Sabine Vettorazzi Ann-Kristin Dorn Florian Mengele Sooyeon Lee Sayantan Nandi Dilay Yilmaz Miriam Stolz Naveen Kumar Tangudu David Carro Vázquez Johanna Pachmayr Ion Cristian Cirstea Maja Vujic Spasic Aspasia Ploubidou Anita Ignatius Jan Tuckermann article Tschaffon2022 A novel in vitro assay to study chondrocyte-to-osteoblast transdifferentiation. PURPOSE: Endochondral ossification, which involves transdifferentiation of chondrocytes into osteoblasts, is an important process involved in the development and postnatal growth of most vertebrate bones as well as in bone fracture healing. To study the basic molecular mechanisms of this process, a robust and easy-to-use in vitro model is desirable. Therefore, we aimed to develop a standardized in vitro assay for the transdifferentiation of chondrogenic cells towards the osteogenic lineage. METHODS: Murine chondrogenic ATDC5 cells were differentiated into the chondrogenic lineage for seven days and subsequently differentiated towards the osteogenic direction. Gene expression analysis of pluripotency, as well as chondrogenic and osteogenic markers, cell-matrix staining, and immunofluorescent staining, were performed to assess the differentiation. In addition, the effects of Wnt3a and lipopolysaccharides (LPS) on the transdifferentiation were tested by their addition to the osteogenic differentiation medium. RESULTS: Following osteogenic differentiation, chondrogenically pe-differentiated cells displayed the expression of pluripotency and osteogenic marker genes as well as alkaline phosphatase activity and a mineralized matrix. Co-expression of Col2a1 and Col1a1 after one day of osteogenic differentiation indicated that osteogenic cells had differentiated from chondrogenic cells. Wnt3a increased and LPS decreased transdifferentiation towards the osteogenic lineage. CONCLUSION: We successfully established a rapid, standardized in vitro assay for the transdifferentiation of chondrogenic cells into osteogenic cells, which is suitable for testing the effects of different compounds on this cellular process. 2022 Jan eng Endocrine 75 266-275 Cartilage to bone transformation, Chondrocyte, Endochondral ossification, Fracture healing, In vitro assay, Transdifferentiation Miriam E. A. Tschaffon Stefan O. Reber Astrid Schoppa Sayantan Nandi Ion C. Cirstea Attila Aszodi Anita Ignatius Melanie Haffner-Luntzer article Stifel2022 Glucocorticoids coordinate macrophage metabolism through the regulation of the tricarboxylic acid cycle. OBJECTIVES: Glucocorticoids (GCs) are one of the most widely prescribed anti-inflammatory drugs. By acting through their cognate receptor, the glucocorticoid receptor (GR), GCs downregulate the expression of pro-inflammatory genes and upregulate the expression of anti-inflammatory genes. Metabolic pathways have recently been identified as key parts of both the inflammatory activation and anti-inflammatory polarization of macrophages, immune cells responsible for acute inflammation and tissue repair. It is currently unknown whether GCs control macrophage metabolism, and if so, to what extent metabolic regulation by GCs confers anti-inflammatory activity. METHODS: Using transcriptomic and metabolomic profiling of macrophages, we identified GC-controlled pathways involved in metabolism, especially in mitochondrial function. RESULTS: Metabolic analyses revealed that GCs repress glycolysis in inflammatory myeloid cells and promote tricarboxylic acid (TCA) cycle flux, promoting succinate metabolism and preventing intracellular accumulation of succinate. Inhibition of ATP synthase attenuated GC-induced transcriptional changes, likely through stalling of TCA cycle anaplerosis. We further identified a glycolytic regulatory transcription factor, HIF1α, as regulated by GCs, and as a key regulator of GC responsiveness during inflammatory challenge. CONCLUSIONS: Our findings link metabolism to gene regulation by GCs in macrophages. 2022 Mar eng Molecular metabolism 57 101424 *Glucocorticoids, *Immunometabolism, *Macrophage, *Succinate, *TCA Cycle Ulrich Stifel Eva-Maria Wolfschmitt Josef Vogt Ulrich Wachter Sabine Vettorazzi Daniel Tews Melanie Hogg Fabian Zink Nora Maria Koll Sandra Winning Rémi Mounier Bénédicte Chazaud Peter Radermacher Pamela Fischer-Posovszky Giorgio Caratti Jan Tuckermann article Ahmed2022 Dexamethasone-mediated inhibition of Notch signalling blocks the interaction of leukaemia and mesenchymal stromal cells. Acute myeloid leukaemia (AML) is a haematological malignancy characterized by a poor prognosis. Bone marrow mesenchymal stromal cells (BM MSCs) support leukaemic cells in preventing chemotherapy-induced apoptosis. This encouraged us to investigate leukaemia-BM niche-associated signalling and to identify signalling cascades supporting the interaction of leukaemic cells and BM MSC. Our study demonstrated functional differences between MSCs originating from leukaemic (AML MSCs) and healthy donors (HD MSCs). The direct interaction of leukaemic and AML MSCs was indispensable in influencing AML cell proliferation. We further identified an important role for Notch expression and its activation in AML MSCs contributing to the enhanced proliferation of AML cells. Supporting this observation, overexpression of the intracellular Notch domain (Notch ICN) in AML MSCs enhanced AML cells' proliferation. From a therapeutic point of view, dexamethasone treatment impeded Notch signalling in AML MSCs resulting in reduced AML cell proliferation. Concurrent with our data, Notch inhibitors had only a marginal effect on leukaemic cells alone but strongly influenced Notch signalling in AML MSCs and abrogated their cytoprotective function on AML cells. In vivo, dexamethasone treatment impeded Notch signalling in AML MSCs leading to a reduced number of AML MSCs and improved survival of leukaemic mice. In summary, targeting the interaction of leukaemic cells and AML MSCs using dexamethasone or Notch inhibitors might further improve treatment outcomes in AML patients. 2022 Feb eng British journal of haematology 196
995-1006 Animals, Anti-Inflammatory Agents/pharmacology/*therapeutic use, Dexamethasone/pharmacology/*therapeutic use, Humans, Leukemia, Myeloid, Acute/*drug therapy, Male, Mesenchymal Stem Cells/*drug effects, Mice, Receptors, Notch/*drug effects, *acute myeloid leukaemia, *bone marrow microenvironment, *dexamethasone, *mesenchymal stromal cell, *notch Helal Mohammed Mohammed Ahmed Subbaiah Chary Nimmagadda Yahya S. Al-Matary Maren Fiori Tobias May Daria Frank Pradeep Kumar Patnana Christian Récher Christoph Schliemann Jan-Henrik Mikesch Thorsten Koenig Frank Rosenbauer Wolfgang Hartmann Jan Tuckermann Ulrich Dührsen Wei Lanying Martin Dugas Bertram Opalka Georg Lenz Cyrus Khandanpour
article Steppe2022 Correction: Steppe et al. Bone Mass and Osteoblast Activity Are Sex-Dependent in Mice Lacking the Estrogen Receptor α in Chondrocytes and Osteoblast Progenitor Cells. , javax.xml.bind.JAXBElement@5271a512, 2022, , javax.xml.bind.JAXBElement@20d7df5a, , 2902. The authors would like to make corrections to the reference citations in the original article [...]. 2022 may 1422-0067 10.3390/ijms23116020 International journal of molecular sciences 23 Lena Steppe Jasmin Bülow Jan Tuckermann Anita Ignatius Melanie Haffner-Luntzer article Steppe2022a Bone Mass and Osteoblast Activity Are Sex-Dependent in Mice Lacking the Estrogen Receptor α in Chondrocytes and Osteoblast Progenitor Cells. While estrogen receptor alpha (ERα) is known to be important for bone development and homeostasis, its exact function during osteoblast differentiation remains unclear. Conditional deletion of ERα during specific stages of osteoblast differentiation revealed different bone phenotypes, which were also shown to be sex-dependent. Since hypertrophic chondrocytes can transdifferentiate into osteoblasts and substantially contribute to long-bone development, we aimed to investigate the effects of ERα deletion in both osteoblast and chondrocytes on bone development and structure. Therefore, we generated mice in which the ERα gene was inactivated via a -driven cyclic recombinase (ERα   ). We analyzed the bones of 3-month-old ERα   mice by biomechanical testing, micro-computed tomography, and cellular parameters by histology. Male ERα   mice displayed a significantly increased cortical bone mass and flexural rigidity of the femurs compared to age-matched controls with no active Cre-transgene (ERα ). By contrast, female ERα   mice exhibited significant trabecular bone loss, whereas in cortical bone periosteal and endosteal diameters were reduced. Our results indicate that the ERα in osteoblast progenitors and hypertrophic chondrocytes differentially contributes to bone mass regulation in male and female mice and improves our understanding of ERα signaling in bone cells in vivo. 2022 mar 1422-0067 10.3390/ijms23052902 International journal of molecular sciences 23 Animals; Chondrocytes; Estrogen Receptor alpha, genetics; Female; Male; Mice; Mice, Knockout; Osteoblasts; Stem Cells; X-Ray Microtomography; biomechanics; bone; chondrocytes; estrogen; genetic animal model; osteoblasts; receptor knockout; sex steroids Lena Steppe Jasmin Bülow Jan Tuckermann Anita Ignatius Melanie Haffner-Luntzer article Nilsson2022 Estradiol and RSPO3 regulate vertebral trabecular bone mass independent of each other. Osteoporosis is an age-dependent serious skeletal disease that leads to great suffering for the patient and high social costs, especially as the global population reaches higher age. Decreasing estrogen levels after menopause result in a substantial bone loss and increased fracture risk, whereas estrogen treatment improves bone mass in women. RSPO3, a secreted protein that modulates WNT signaling, increases trabecular bone mass and strength in the vertebrae of mice, and is associated with trabecular density and risk of distal forearm fractures in humans. The aim of the present study was to determine if RSPO3 is involved in the bone-sparing effect of estrogens. We first observed that estradiol (E2) treatment increases RSPO3 expression in bone of ovariectomized (OVX) mice, supporting a possible role of RSPO3 in the bone-sparing effect of estrogens. As RSPO3 is mainly expressed by osteoblasts in the bone, we used a mouse model devoid of osteoblast-derived RSPO3 (Runx2-creRspo3(flox/flox) mice) to determine if RSPO3 is required for the bone-sparing effect of E2 in OVX mice. We confirmed that osteoblast-specific RSPO3 inactivation results in a substantial reduction in trabecular bone mass and strength in the vertebrae. However, E2 increased vertebral trabecular bone mass and strength similarly in mice devoid of osteoblast-derived RSPO3 and control mice. Unexpectedly, osteoblast-derived RSPO3 was needed for the full estrogenic response on cortical bone thickness. In conclusion, although osteoblast-derived RSPO3 is a crucial regulator of vertebral trabecular bone, it is required for a full estrogenic effect on cortical, but not trabecular, bone in OVX mice. Thus, estradiol and RSPO3 regulate vertebral trabecular bone mass independent of each other.NEW & NOTEWORTHY Osteoblast-derived RSPO3 is known to be a crucial regulator of vertebral trabecular bone. Our new findings show that RSPO3 and estrogen regulate trabecular bone independent of each other, but that RSPO3 is necessary for a complete estrogenic effect on cortical bone. 2022 mar eng American journal of physiology. Endocrinology and metabolism 322
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E211-E218 RSPO3, estrogen, trabecular bone Karin H. Nilsson Jianyao Wu Karin L. Gustafsson Maha El Shahawy Antti Koskela Juha Tuukkanen Jan Tuckermann Petra Henning Ulf H. Lerner Claes Ohlsson Sofia Movérare-Skrtic
article The endothelium-bone axis in development, homeostasis and bone and joint disease 2021 10 17 Nat Rev Rheumatol . 17(10) 608-620 J. Tuckermann R. H. Adams article A novel in vitro assay to study chondrocyte-to-osteoblast transdifferentiation 2021 9 16 Endocrine Miriam E. A. Tschaffon S. O. Reber Astrid Schoppa S. Nandi I. C. Cirstea Attila Aszodi A Ignatius M Haffner-Luntzer article Deletion of Cdk5 in Macrophages Ameliorates Anti-Inflammatory Response during Endotoxemia through Induction of C-Maf and Il-10 2021 9 6 Int J Mol Sci . 22(17):9648 P. Pfänder U. Burret S. Vettorazzi A.-K. Eiers article RSPO3 is important for trabecular bone and fracture risk in mice and humans 2021 8 13 Nat Commun. 12(1) 4923 KH. Nilsson M. Nethander A. Koskela J. Tuukkanen PPC. Souza J. Tuckermann U. H. Lerner S. Movérare-Skrtic C. Ohlsson J. B. Richards S. Zhou P. Henning M. E. Shahawy T. L. Andersen C. Ejersted J. Wu K. L. Gustafsson M. Lorentzon L. E. Ruud J. H. Tobias article A guide to changing paradigms of glucocorticoid receptor function-a model system for genome regulation and physiology 2021 7 2 The FEBS journal S. Vettorazzi J. Tuckermann C. Gebhardt D. Nalbantoglu article Shaping the bone through iron and iron-related proteins 2021 6 27 Semin Hematol 58(3) 188-200 M. Vujić Spasić L. C. Hofbauer U. Baschant M. Rauner M. G. Ledesma-Colunga H. Weidner article Inhibition of sphingosine 1-phosphate protects mice against chondrocyte catabolism and osteoarthritis 2021 6 16 Osteoarthritis Cartilage 29(9) 1335-1345 S. Vettorazzi J. Tuckermann C Cherifi A Latourte J Casas O Cuvillier P Richette A Ostertag M Cohen-Solal E Hay S Provot H-K Ea A Ledoux article HAND2 is a novel obesity-linked adipogenic transcription factor regulated by glucocorticoid signalling 2021 5 20 Diabetologia 64(8) 1850-1865 J. Tuckermann G. Caratti M. Giroud FF Tsokanos S Kotschi S Khani C Jouffe E. Vogl M. Irmler C Glantschnig M Gil-Lozano D Hass MR Garcia F Mattijssen A Maida D Tews P Fischer-Posovszky KA Virtanen J Beckers M Wabitsch H Uhlenhaut M Blüher M Scheideler A Bartelt S Herzig A Feuchtinger AA Khan article Sorting Nexin 10 as a Key Regulator of Membrane Trafficking in Bone-Resorbing Osteoclasts: Lessons Learned From Osteopetrosis 2021 5 20 Front Cell Dev Biol. 9:671210 M. Barnea-Zohar S. Winograd-Katz N. Reuven M. Shalev M. Kanaan J. Tuckermann B. Geiger A Elson M Stein G Rabie J Sekeres article Iron at the Interface of Hepatocellular Carcinoma 2021 04 15 Int. J. Mol. Sci. 8 22 R. Paganoni A. Lechel M. Vujić Spasić article An SNX10-dependent mechanism down-regulates fusion between mature osteoclasts 2021 04 01 J Cell Sci . M. Barnea-Zohar S. Winograd-Katz M. Shalev E. Arman N. Reuven L. Roth O. Golani M. Stein F. Thalji M. Kanaan J. Tuckermann B. Geiger A. Elson article Leukemia inhibitory factor treatment attenuates the detrimental effects of glucocorticoids on bone in mice 2021 04 Bone. 145 115843 S. Lee P. Liu M. Ahmad J. P. Tuckermann article Senescence in RASopathies, a possible novel contributor to a complex pathophenoype 2021 03 Mech Ageing Dev. 194 111411 M. Engler M. Fidan S. Nandi I. C. Cirstea article PTPRJ promotes osteoclast maturation and activity by inhibiting Cbl-mediated ubiquitination of NFATc1 in late osteoclastogenesis 2021 02 19 FEBS J. M. Shalev E. Arman M. Stein Y. Cohen-Sharir V. Brumfeld S. Kapishnikov I. Royal J. Tuckermann A. Elson article Intact Glucocorticoid Receptor Dimerization Is Deleterious in Trauma-Induced Impaired Fracture Healing 2021 02 17 Front Immunol. 11 628287 Y. Hachemi A. E. Rapp A.-K. Dorn S. Lee B. T. Krüger K. Kaiser A. Ignatius J. Tuckermann article A physiological glucocorticoid rhythm is an important regulator of brown adipose tissue function 2021 02 03 Mol Metab. 47 101179 J. Kroon M. Schilperoort W. In Het Panhuis R. van den Berg L. van Doeselaar C. R C Verzijl N. van Trigt IM. Mol HCM. Sips J. K. van den Heuvel L. L. Koorneef R. J. van der Sluis A. Fenzl F. W. Kiefer S. Vettorazzi J. P. Tuckermann N. R. Biermasz OC. Meijer P. C N Rensen S. Kooijman article RNF40 exerts stage-dependent functions in differentiating osteoblasts and is essential for bone cell crosstalk 2021 02 Cell Death Diff. 28 700-714 2 Z. Najafova P. Liu F. Wegwitz M. Ahmad L. Tamon R. L. Kosinsky W. Xie S. A. Johnsen J. Tuckermann article Nilsson2021 RSPO3 is important for trabecular bone and fracture risk in mice and humans. With increasing age of the population, countries across the globe are facing a substantial increase in osteoporotic fractures. Genetic association signals for fractures have been reported at the RSPO3 locus, but the causal gene and the underlying mechanism are unknown. Here we show that the fracture reducing allele at the RSPO3 locus associate with increased RSPO3 expression both at the mRNA and protein levels, increased trabecular bone mineral density and reduced risk mainly of distal forearm fractures in humans. We also demonstrate that RSPO3 is expressed in osteoprogenitor cells and osteoblasts and that osteoblast-derived RSPO3 is the principal source of RSPO3 in bone and an important regulator of vertebral trabecular bone mass and bone strength in adult mice. Mechanistic studies revealed that RSPO3 in a cell-autonomous manner increases osteoblast proliferation and differentiation. In conclusion, RSPO3 regulates vertebral trabecular bone mass and bone strength in mice and fracture risk in humans. 2021 aug 2041-1723 10.1038/s41467-021-25124-2 Nature communications 12 4923 Animals; Bone Density; Cancellous Bone, injuries, metabolism; Cell Differentiation, genetics; Cell Proliferation, genetics; Cells, Cultured; Fractures, Bone, genetics; Genetic Predisposition to Disease, genetics; Humans; Mendelian Randomization Analysis, methods; Mice, Knockout; Mice, Transgenic; Osteoblasts, cytology, metabolism; Polymorphism, Single Nucleotide; Risk Factors; Thrombospondins, deficiency, genetics Karin H. Nilsson Petra Henning Maha El Shahawy Maria Nethander Thomas Levin Andersen Charlotte Ejersted Jianyao Wu Karin L. Gustafsson Antti Koskela Juha Tuukkanen Pedro P. C. Souza Jan Tuckermann Mattias Lorentzon Linda Engström Ruud Terho Lehtimäki Jon H. Tobias Sirui Zhou Ulf H. Lerner J. Brent Richards Sofia Movérare-Skrtic Claes Ohlsson article Studying Metabolic Abnormalities in the Costello Syndrome HRAS G12V Mouse Model: Isolation of Mouse Embryonic Fibroblasts and Their In Vitro Adipocyte Differentiation 2021 Methods Mol Biol. 2262 397-409 Ion C. Cirstea Miray Fidan S Chennappan article Engler2021 Senescence in RASopathies, a possible novel contributor to a complex pathophenoype. Senescence is a biological process that induces a permanent cell cycle arrest and a specific gene expression program in response to various stressors. Following studies over the last few decades, the concept of senescence has evolved from an antiproliferative mechanism in cancer (oncogene-induced senescence) to a critical component of physiological processes associated with embryonic development, tissue regeneration, ageing and its associated diseases. In somatic cells, oncogenic mutations in RAS-MAPK pathway genes are associated with oncogene-induced senescence and cancer, while germline mutations in the same pathway are linked to a group of monogenic developmental disorders generally termed RASopathies. Here, we consider that in these disorders, senescence induction may result in opposing outcomes, a tumour protective effect and a possible contributor to a premature ageing phenotype identified in Costello syndrome, which belongs to the RASopathy group. In this review, we will highlight the role of senescence in organismal homeostasis and we will describe the current knowledge about senescence in RASopathies. Additionally, we provide a perspective on examples of experimentally characterised RASopathy mutations that, alone or in combination with various stressors, may also trigger an age-dependent chronic senescence, possibly contributing to the age-dependent worsening of RASopathy pathophenotype and the reduction of lifespan. 2021 mar 1872-6216 10.1016/j.mad.2020.111411 Mechanisms of ageing and development 194 111411 Age Factors; Aging, genetics, metabolism, pathology; Aging, Premature, genetics, metabolism, pathology; Animals; Cell Differentiation; Cell Proliferation; Cellular Senescence; Costello Syndrome, genetics, metabolism, pathology; Ectodermal Dysplasia, genetics, metabolism, pathology; Facies; Failure to Thrive, genetics, metabolism, pathology; Genetic Predisposition to Disease; Heart Defects, Congenital, genetics, metabolism, pathology; Humans; Mitogen-Activated Protein Kinases, metabolism; Mutation; Noonan Syndrome, genetics, metabolism, pathology; Phenotype; Signal Transduction; ras Proteins, genetics, metabolism; Cardio-facio-cutaneous syndrome; Costello syndrome; Germline mutations; Noonan syndrome; Oncogene-induced senescence; Premature ageing; RAS-MAPK; RASopathy; Senescence Melanie Engler Miray Fidan Sayantan Nandi Ion Cristian Cirstea article Elson2021 Sorting Nexin 10 as a Key Regulator of Membrane Trafficking in Bone-Resorbing Osteoclasts: Lessons Learned From Osteopetrosis. Bone homeostasis is a complex, multi-step process, which is based primarily on a tightly orchestrated interplay between bone formation and bone resorption that is executed by osteoblasts and osteoclasts (OCLs), respectively. The essential physiological balance between these cells is maintained and controlled at multiple levels, ranging from regulated gene expression to endocrine signals, yet the underlying cellular and molecular mechanisms are still poorly understood. One approach for deciphering the mechanisms that regulate bone homeostasis is the characterization of relevant pathological states in which this balance is disturbed. In this article we describe one such "error of nature," namely the development of acute recessive osteopetrosis (ARO) in humans that is caused by mutations in sorting nexin 10 (SNX10) that affect OCL functioning. We hypothesize here that, by virtue of its specific roles in vesicular trafficking, SNX10 serves as a key selective regulator of the composition of diverse membrane compartments in OCLs, thereby affecting critical processes in the sequence of events that link the plasma membrane with formation of the ruffled border and with extracellular acidification. As a result, SNX10 determines multiple features of these cells either directly or, as in regulation of cell-cell fusion, indirectly. This hypothesis is further supported by the similarities between the cellular defects observed in OCLs form various models of ARO, induced by mutations in SNX10 and in other genes, which suggest that mutations in the known ARO-associated genes act by disrupting the same plasma membrane-to-ruffled border axis, albeit to different degrees. In this article, we describe the population genetics and spread of the original arginine-to-glutamine mutation at position 51 (R51Q) in SNX10 in the Palestinian community. We further review recent studies, conducted in animal and cellular model systems, that highlight the essential roles of SNX10 in critical membrane functions in OCLs, and discuss possible future research directions that are needed for challenging or substantiating our hypothesis. 2021 2296-634X 10.3389/fcell.2021.671210 Frontiers in cell and developmental biology 9 671210 ARO; SNX10; bone resorption; osteoclast; osteopetrosis; sorting nexin Ari Elson Merle Stein Grace Rabie Maayan Barnea-Zohar Sabina Winograd-Katz Nina Reuven Moran Shalev Juraj Sekeres Moien Kanaan Jan Tuckermann Benjamin Geiger article Tuckermann2021 The endothelium-bone axis in development, homeostasis and bone and joint disease. Blood vessels form a versatile transport network that is best known for its critical roles in processes such as tissue oxygenation, metabolism and immune surveillance. The vasculature also provides local, often organ-specific, molecular signals that control the behaviour of other cell types in their vicinity during development, homeostasis and regeneration, and also in disease processes. In the skeletal system, the local vasculature is actively involved in both bone formation and resorption. In addition, blood vessels participate in inflammatory processes and contribute to the pathogenesis of diseases that affect the joints, such as rheumatoid arthritis and osteoarthritis. This Review summarizes the current understanding of the architecture, angiogenic growth and functional properties of the bone vasculature. The effects of ageing and pathological conditions, including arthritis and osteoporosis, are also discussed. 2021 oct 1759-4804 10.1038/s41584-021-00682-3 Nature reviews. Rheumatology 17 608--620 Aging, physiology; Animals; Arthritis, physiopathology; Bone Development, physiology; Bone Diseases, drug therapy, physiopathology; Bone Regeneration, drug effects, physiology; Bone and Bones, blood supply, physiology, physiopathology; Chondrocytes, physiology; Endothelium, Vascular, physiology, physiopathology; Fractures, Bone, physiopathology; Homeostasis, physiology; Humans; Joint Diseases, drug therapy, physiopathology; Macrophages, physiology; Mice; Neovascularization, Pathologic, drug therapy, physiopathology; Neovascularization, Physiologic, physiology; Osteoblasts, physiology; Osteogenesis, physiology; Osteoporosis, drug therapy, physiopathology; Receptor Cross-Talk, physiology; Synoviocytes, physiology Jan Tuckermann Ralf H. Adams article Reichardt2021 The Role of Glucocorticoids in Inflammatory Diseases. For more than 70 years, glucocorticoids (GCs) have been a powerful and affordable treatment option for inflammatory diseases. However, their benefits do not come without a cost, since GCs also cause side effects. Therefore, strong efforts are being made to improve their therapeutic index. In this review, we illustrate the mechanisms and target cells of GCs in the pathogenesis and treatment of some of the most frequent inflammatory disorders affecting the central nervous system, the gastrointestinal tract, the lung, and the joints, as well as graft-versus-host disease, which often develops after hematopoietic stem cell transplantation. In addition, an overview is provided of novel approaches aimed at improving GC therapy based on chemical modifications or GC delivery using nanoformulations. GCs remain a topic of highly active scientific research despite being one of the oldest class of drugs in medical use. 2021 Oct eng Cells 10 Animals, Disease Models, Animal, Glucocorticoids/*metabolism, Humans, Inflammation/*metabolism/pathology, Models, Biological, Nanoparticles/chemistry, Phenotype, *acute lung injury, *asthma, *glucocorticoid receptor, *graft-versus-host-disease, *inflammatory bowel disease, *multiple sclerosis, *nanoparticles, *rheumatoid arthritis Sybille D. Reichardt Agathe Amouret Chiara Muzzi Sabine Vettorazzi Jan P. Tuckermann Fred Lühder Holger M. Reichardt article Najafova2021 RNF40 exerts stage-dependent functions in differentiating osteoblasts and is essential for bone cell crosstalk. The role of histone ubiquitination in directing cell lineage specification is only poorly understood. Our previous work indicated a role of the histone 2B ubiquitin ligase RNF40 in controlling osteoblast differentiation in vitro. Here, we demonstrate that RNF40 has a stage-dependent function in controlling osteoblast differentiation in vivo. RNF40 expression is essential for early stages of lineage specification, but is dispensable in mature osteoblasts. Paradoxically, while osteoblast-specific RNF40 deletion led to impaired bone formation, it also resulted in increased bone mass due to impaired bone cell crosstalk. Loss of RNF40 resulted in decreased osteoclast number and function through modulation of RANKL expression in OBs. Mechanistically, we demonstrate that Tnfsf11 (encoding RANKL) is an important target gene of H2B monoubiquitination. These data reveal an important role of RNF40-mediated H2B monoubiquitination in bone formation and remodeling and provide a basis for exploring this pathway for the treatment of conditions such as osteoporosis or cancer-associated osteolysis. 2021 feb 1476-5403 10.1038/s41418-020-00614-w Cell death and differentiation 28 700--714 Animals; Cell Differentiation; Histones, metabolism; Male; Mice; Mice, Inbred C57BL; Osteocytes, metabolism; Osteogenesis, physiology; RANK Ligand, genetics, metabolism; Ubiquitin-Protein Ligases, genetics, metabolism; Ubiquitination, physiology Zeynab Najafova Peng Liu Florian Wegwitz Mubashir Ahmad Liezel Tamon Robyn Laura Kosinsky Wanhua Xie Steven A. Johnsen Jan Tuckermann article Fidan2021 Studying Metabolic Abnormalities in the Costello Syndrome HRAS G12V Mouse Model: Isolation of Mouse Embryonic Fibroblasts and Their In Vitro Adipocyte Differentiation. Costello syndrome (CS), characterized by a developmental delay and a failure to thrive, is also associated with an impaired lipid and energy metabolism. White adipose tissue is a central sensor of whole-body energy homeostasis, and HRAS hyperactivation may affect adipocyte differentiation and mature adipocyte homeostasis. An extremely useful tool for delineating in vitro intrinsic cellular signaling leading to metabolic alterations during adipogenesis is mouse embryonic fibroblasts, known to differentiate into adipocytes in response to adipogenesis-stimulating factors. Here, we describe in detail the isolation and maintenance of CS HRAS G12V mouse embryonic fibroblasts, their differentiation into adipocytes, and an assessment of adipocyte differentiation. 2021 1940-6029 10.1007/978-1-0716-1190-6_24 Methods in molecular biology (Clifton, N.J.) 2262 397--409 Adipocytes, metabolism, pathology; Adipogenesis; Animals; Cell Differentiation; Costello Syndrome, genetics, metabolism, pathology; Disease Models, Animal; Embryo, Mammalian, metabolism, pathology; Female; Fibroblasts, metabolism, pathology; Homeostasis; In Vitro Techniques; Male; Mice; Mice, Knockout; Mutation; Proto-Oncogene Proteins p21(ras), physiology; Adipocyte; Costello syndrome; Development; Embryonic; Fibroblast; Metabolism; Mouse model; RASopathy Miray Fidan Saravanakkumar Chennappan Ion Cristian Cirstea article Shalev2021 PTPRJ promotes osteoclast maturation and activity by inhibiting Cbl-mediated ubiquitination of NFATc1 in late osteoclastogenesis. Bone-resorbing osteoclasts (OCLs) are multinucleated phagocytes, whose central roles in regulating bone formation and homeostasis are critical for normal health and development. OCLs are produced from precursor monocytes in a multistage process that includes initial differentiation, cell-cell fusion, and subsequent functional and morphological maturation; the molecular regulation of osteoclastogenesis is not fully understood. Here, we identify the receptor-type protein tyrosine phosphatase PTPRJ as an essential regulator specifically of OCL maturation. Monocytes from PTPRJ-deficient (JKO) mice differentiate and fuse normally, but their maturation into functional OCLs and their ability to degrade bone are severely inhibited. In agreement, mice lacking PTPRJ throughout their bodies or only in OCLs exhibit increased bone mass due to reduced OCL-mediated bone resorption. We further show that PTPRJ promotes OCL maturation by dephosphorylating the M-CSF receptor (M-CSFR) and Cbl, thus reducing the ubiquitination and degradation of the key osteoclastogenic transcription factor NFATc1. Loss of PTPRJ increases ubiquitination of NFATc1 and reduces its amounts at later stages of osteoclastogenesis, thereby inhibiting OCL maturation. PTPRJ thus fulfills an essential and cell-autonomous role in promoting OCL maturation by balancing between the pro- and anti-osteoclastogenic activities of the M-CSFR and maintaining NFATc1 expression during late osteoclastogenesis. 2021 aug 1742-4658 10.1111/febs.15778 The FEBS journal 288 4702--4723 Animals; Cells, Cultured; Female; Male; Mice; Mice, Inbred C57BL; Monocytes, cytology, metabolism; NFATC Transcription Factors, metabolism; Osteoclasts, cytology, metabolism; Osteogenesis; Proto-Oncogene Proteins c-cbl, metabolism; Receptor, Macrophage Colony-Stimulating Factor, metabolism; Receptor-Like Protein Tyrosine Phosphatases, Class 3, genetics, metabolism; Ubiquitination; Cbl; DEP-1; PTPRJ; osteoclast; protein tyrosine phosphatase Moran Shalev Esther Arman Merle Stein Yael Cohen-Sharir Vlad Brumfeld Sergey Kapishnikov Isabelle Royal Jan Tuckermann Ari Elson article Steppe2021 Estrogen Receptor α Signaling in Osteoblasts is Required for Mechanotransduction in Bone Fracture Healing. Biomechanical stimulation by whole-body low-magnitude high-frequency vibration (LMHFV) has demonstrated to provoke anabolic effects on bone metabolism in both non-osteoporotic and osteoporotic animals and humans. However, preclinical studies reported that vibration improved fracture healing and bone formation in osteoporotic, ovariectomized (OVX) mice representing an estrogen-deficient hormonal status, but impaired bone regeneration in skeletally healthy non-OVX mice. These effects were abolished in general estrogen receptor α (ERα)-knockout (KO) mice. However, it remains to be elucidated which cell types in the fracture callus are targeted by LMHFV during bone healing. To answer this question, we generated osteoblast lineage-specific ERα-KO mice that were subjected to ovariectomy, femur osteotomy and subsequent vibration. We found that the ERα specifically on osteoblastic lineage cells facilitated the vibration-induced effects on fracture healing, because in osteoblast lineage-specific ERα-KO (ERα(fl/fl; Runx2Cre)) mice the negative effects in non-OVX mice were abolished, whereas the positive effects of vibration in OVX mice were reversed. To gain greater mechanistic insights, the influence of vibration on murine and human osteogenic cells was investigated in vitro by whole genome array analysis and qPCR. The results suggested that particularly canonical WNT and Cox2/PGE(2) signaling is involved in the mechanotransduction of LMHFV under estrogen-deficient conditions. In conclusion, our study demonstrates a critical role of the osteoblast lineage-specific ERα in LMHFV-induced effects on fracture healing and provides further insights into the molecular mechanism behind these effects. 2021 eng Frontiers in bioengineering and biotechnology 9 782355 LMHFV, estrogen receptor signaling, fracture healing, osteoblasts, prostaglandin signaling, whole-body vibration, wnt signaling Lena Steppe Benjamin Thilo Krüger Miriam Eva Angelica Tschaffon Verena Fischer Jan Tuckermann Anita Ignatius Melanie Haffner-Luntzer article Kroon2021 A physiological glucocorticoid rhythm is an important regulator of brown adipose tissue function. Brown adipose tissue (BAT) displays a strong circadian rhythm in metabolic activity, but it is unclear how this rhythm is regulated. As circulating levels of corticosterone coincide with the rhythm of triglyceride-derived fatty acid (FA) uptake by BAT, we investigated whether corticosterone regulates BAT circadian rhythm. Corticosterone levels were flattened by implanting mice with subcutaneous corticosterone-releasing pellets, resulting in constant circulating corticosterone levels. Flattened corticosterone rhythm caused a complete loss of circadian rhythm in triglyceride-derived fatty acid uptake by BAT. This effect was independent of glucocorticoid receptor expression in (brown) adipocytes and was not caused by deregulation of clock gene expression or overexposure to glucocorticoids, but rather seemed mediated by reduced sympathetic innervation of BAT. In a mouse model of hyperlipidemia and metabolic syndrome, long-term experimental flattening of corticosterone - and thus rhythm in BAT function - resulted in adiposity. This study highlights that a physiological rhythm in glucocorticoids is an important regulator of BAT function and essential for the maintenance of metabolic health. 2021 may 2212-8778 10.1016/j.molmet.2021.101179 Molecular metabolism 47 101179 Adipocytes, metabolism, pathology; Adipose Tissue, Brown, metabolism, pathology; Adiposity; Animals; Circadian Rhythm, physiology; Corticosterone, metabolism; Fatty Acids, metabolism; Female; Glucocorticoids, metabolism; Lipid Metabolism, physiology; Male; Mice; Mice, Inbred C57BL; Obesity, metabolism; Period Circadian Proteins, genetics, metabolism; Receptors, Glucocorticoid, genetics, metabolism; Transcriptome; Triglycerides, metabolism; Brown adipose tissue; Circadian Rhythm; Corticosterone; Glucocorticoid receptor Jan Kroon Maaike Schilperoort Wietse In Het Panhuis Rosa Berg Lotte Doeselaar Cristy R. C. Verzijl Nikki Trigt Isabel M. Mol Hetty H. C. M. Sips Jose K. Heuvel Lisa L. Koorneef Ronald J. Sluis Anna Fenzl Florian W. Kiefer Sabine Vettorazzi Jan P. Tuckermann Nienke R. Biermasz Onno C. Meijer Patrick C. N. Rensen Sander Kooijman article BarneaZohar2021 An SNX10-dependent mechanism downregulates fusion between mature osteoclasts. Homozygosity for the R51Q mutation in sorting nexin 10 (SNX10) inactivates osteoclasts (OCLs) and induces autosomal recessive osteopetrosis in humans and in mice. We show here that the fusion of wild-type murine monocytes to form OCLs is highly regulated, and that its extent is limited by blocking fusion between mature OCLs. In contrast, monocytes from homozygous R51Q SNX10 mice fuse uncontrollably, forming giant dysfunctional OCLs that can become 10- to 100-fold larger than their wild-type counterparts. Furthermore, mutant OCLs display reduced endocytotic activity, suggesting that their deregulated fusion is due to alterations in membrane homeostasis caused by loss of SNX10 function. This is supported by the finding that the R51Q SNX10 protein is unstable and exhibits altered lipid-binding properties, and is consistent with a key role for SNX10 in vesicular trafficking. We propose that OCL size and functionality are regulated by a cell-autonomous SNX10-dependent mechanism that downregulates fusion between mature OCLs. The R51Q mutation abolishes this regulatory activity, leading to excessive fusion, loss of bone resorption capacity and, consequently, to an osteopetrotic phenotype in vivo. This article has an associated First Person interview with the joint first authors of the paper. 2021 may 1477-9137 10.1242/jcs.254979 Journal of cell science 134 Animals; Bone Resorption, genetics; Mice; Mutation, genetics; Osteoclasts; Osteopetrosis; Sorting Nexins, genetics; Bone; Cell fusion; Osteoclast; Osteopetrosis; SNX10 Maayan Barnea-Zohar Sabina E. Winograd-Katz Moran Shalev Esther Arman Nina Reuven Lee Roth Ofra Golani Merle Stein Fadi Thalji Moien Kanaan Jan Tuckermann Benjamin Geiger Ari Elson article Vettorazzi2021 A guide to changing paradigms of glucocorticoid receptor function-a model system for genome regulation and physiology. The glucocorticoid receptor (GR) is a bona fide ligand-regulated transcription factor. Cloned in the 80s, the GR has become one of the best-studied and clinically most relevant members of the nuclear receptor superfamily. Cooperative activity of GR with other transcription factors and a plethora of coregulators contribute to the tissue- and context-specific response toward the endogenous and pharmacological glucocorticoids (GCs). Furthermore, nontranscriptional activities in the cytoplasm are emerging as an additional function of GR. Over the past 40 years, the concepts of GR mechanisms of action had been constantly changing. Different methodologies in the pregenomic and genomic era of molecular biological research and recent cutting-edge technology in single-cell and single-molecule analysis are steadily evolving the views, how the GR in particular and transcriptional regulation in general act in physiological and pathological processes. In addition to the development of technologies for GR analysis, the use of model organisms provides insights how the GR in vivo executes GC action in tissue homeostasis, inflammation, and energy metabolism. The model organisms, namely the mouse, but also rats, zebrafish, and recently fruit flies carrying mutations of the GR became a major driving force to analyze the molecular function of GR in disease models. This guide provides an overview of the exciting research and paradigm shifts in the GR field from past to present with a focus on GR transcription factor networks, GR DNA-binding and single-cell analysis, and model systems. 2021 jul 1742-4658 10.1111/febs.16100 The FEBS journal genomic action; glucocorticoid receptor; nongenomic action; nuclear receptor; single-molecule analysis; transcription factor Sabine Vettorazzi Denis Nalbantoglu J. Christof M. Gebhardt Jan Tuckermann article Lee2021 Distinct Glucocorticoid Receptor Actions in Bone Homeostasis and Bone Diseases. Glucocorticoids (GCs) are steroid hormones that respond to stress and the circadian rhythm. Pharmacological GCs are widely used to treat autoimmune and chronic inflammatory diseases despite their adverse effects on bone after long-term therapy. GCs regulate bone homeostasis in a cell-type specific manner, affecting osteoblasts, osteoclasts, and osteocytes. Endogenous physiological and exogenous/excessive GCs act via nuclear receptors, mainly via the GC receptor (GR). Endogenous GCs have anabolic effects on bone mass regulation, while excessive or exogenous GCs can cause detrimental effects on bone. GC-induced osteoporosis (GIO) is a common adverse effect after GC therapy, which increases the risk of fractures. Exogenous GC treatment impairs osteoblastogenesis, survival of the osteoblasts/osteocytes and prolongs the longevity of osteoclasts. Under normal physiological conditions, endogenous GCs are regulated by the circadian rhythm and circadian genes display oscillatory rhythmicity in bone cells. However, exogenous GCs treatment disturbs the circadian rhythm. Recent evidence suggests that the disturbed circadian rhythm by continuous exogenous GCs treatment can in itself hamper bone integrity. GC signaling is also important for fracture healing and rheumatoid arthritis, where crosstalk among several cell types including macrophages and stromal cells is indispensable. This review summarizes the complexity of GC actions via GR in bone cells at cellular and molecular levels, including the effect on circadian rhythmicity, and outlines new therapeutic possibilities for the treatment of their adverse effects. 2021 eng Frontiers in endocrinology 12 815386 *glucocorticoid receptor, *osteoblast, *osteoclast, *osteoporosis, *transgenic mice Sooyeon Lee Benjamin Thilo Krüger Anita Ignatius Jan Tuckermann article Nairz2021 Cell-specific expression of determines the outcome of Salmonella enterica serovar Typhimurium infection in mice. Mutations in HFE cause hereditary hemochromatosis type I hallmarked by increased iron absorption, iron accumulation in hepatocytes and iron deficiency in myeloid cells. HFE encodes an MHC-I like molecule, but its function in immune responses to infection remains incompletely understood. Here, we investigated putative roles of Hfe in myeloid cells and hepatocytes, separately, upon infection with Salmonella Typhimurium, an intracellular bacterium with iron-dependent virulence. We found that constitutive and macrophage-specific deletion of Hfe protected infected mice. The propagation of Salmonella in macrophages was reduced due to limited intramacrophage iron availability for bacterial growth and increased expression of the anti-microbial enzyme nitric oxide synthase-2. By contrast, mice with hepatocyte-specific deletion of Hfe succumbed earlier to Salmonella infection because of unrestricted extracellular bacterial replication associated with high iron availability in the serum and impaired expression of essential host defense molecules such as interleukin-6, interferon-γ and nitric oxide synthase-2. Wild-type mice subjected to dietary iron overload phenocopied hepatocyte-specific Hfe deficiency suggesting that increased iron availability in the serum is deleterious in Salmonella infection and underlies impaired host immune responses. Moreover, the macrophage-specific effect is dominant over hepatocyte-specific Hfe-depletion, as Hfe knock-out mice have increased survival despite the higher parenchymal iron load associated with systemic loss of Hfe. We conclude that cell-specific expression of Hfe in hepatocytes and macrophages differentially affects the course of infections with specific pathogens by determining bacterial iron access and the efficacy of anti-microbial immune effector pathways. This may explain the high frequency and evolutionary conservation of human HFE mutations. 2021 Dec eng Haematologica 106 3149-3161 Animals, *Hemochromatosis, Hemochromatosis Protein/genetics, Mice, Knockout, *Salmonella Infections/genetics, Salmonella typhimurium/genetics, Serogroup Manfred Nairz Christoph Metzendorf Maja Vujic-Spasic Anna-Maria Mitterstiller Andrea Schroll David Haschka Alexander Hoffmann Laura Von Raffay Richard Sparla Christian W. Huck Heribert Talasz Patrizia L. Moser Martina U. Muckenthaler Günter Weiss article Giroud2021 HAND2 is a novel obesity-linked adipogenic transcription factor regulated by glucocorticoid signalling. Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we investigate the role of heart and neural crest derivatives-expressed 2 (HAND2) in adipogenesis. Human white adipose tissue (WAT) was collected from two cross-sectional studies of 318 and 96 individuals. In vitro, for mechanistic experiments we used primary adipocytes from humans and mice as well as human multipotent adipose-derived stem (hMADS) cells. Gene silencing was performed using siRNA or genetic inactivation in primary adipocytes from loxP and or tamoxifen-inducible Cre-ERT2 mouse models with Cre-encoding mRNA or tamoxifen, respectively. Adipogenesis and adipocyte metabolism were measured by Oil Red O staining, quantitative PCR (qPCR), microarray, glucose uptake assay, western blot and lipolysis assay. A combinatorial RNA sequencing (RNAseq) and ChIP qPCR approach was used to identify target genes regulated by HAND2. In vivo, we created a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter (Hand2 ) and performed a large panel of metabolic tests. We found that HAND2 is an obesity-linked white adipocyte transcription factor regulated by glucocorticoids that was necessary but insufficient for adipocyte differentiation in vitro. In a large cohort of humans, WAT HAND2 expression was correlated to BMI. The HAND2 gene was enriched in white adipocytes compared with brown, induced early in differentiation and responded to dexamethasone (DEX), a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in hMADS cells or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that adipocyte HAND2 is regulated by glucocorticoids via GR in vitro and in vivo. Furthermore, we identified gene clusters indirectly regulated by the GR-HAND2 pathway. Interestingly, silencing of HAND2 impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that HAND2 was required at stages prior to Adipoq expression. In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in humans and mice. Array data have been submitted to the GEO database at NCBI (GSE148699). 2021 aug 1432-0428 10.1007/s00125-021-05470-y Diabetologia 64 1850--1865 Adipocytes, metabolism; Adipogenesis, physiology; Adipose Tissue, Brown, metabolism; Adult; Aged; Animals; Basic Helix-Loop-Helix Transcription Factors, genetics; Cross-Sectional Studies; Female; Gene Expression Regulation, physiology; Gene Silencing; Glucocorticoids, pharmacology; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Obesity, genetics; Real-Time Polymerase Chain Reaction; Signal Transduction; Transcription Factors, genetics; Young Adult; Adipocytes; Dexamethasone; Differentiation; Glucocorticoid receptor; HAND2; Human adipose tissue; Mesenchymal stem cells; Obesity; Transcription factor; hMADS Maude Giroud Foivos-Filippos Tsokanos Giorgio Caratti Stefan Kotschi Sajjad Khani Céline Jouffe Elena S. Vogl Martin Irmler Christina Glantschnig Manuel Gil-Lozano Daniela Hass Asrar Ali Khan Marcos Rios Garcia Frits Mattijssen Adriano Maida Daniel Tews Pamela Fischer-Posovszky Annette Feuchtinger Kirsi A. Virtanen Johannes Beckers Martin Wabitsch Henriette Uhlenhaut Matthias Blüher Jan Tuckermann Marcel Scheideler Alexander Bartelt Stephan Herzig article Preuss2021 Impaired Glucocorticoid Receptor Signaling Aggravates Lung Injury after Hemorrhagic Shock. We previously showed that attenuated lung injury after hemorrhagic shock (HS) coincided with enhanced levels of the glucocorticoid (GC) receptor (GR) in lung tissue of swine. Here, we investigated the effects of impaired GR signaling on the lung during resuscitated HS using a dysfunctional GR mouse model (GR(dim/dim)). In a mouse intensive care unit, HS led to impaired lung mechanics and aggravated lung inflammation in GR(dim/dim) mice compared to wildtype mice (GR(+/+)). After HS, high levels of the pro-inflammatory and pro-apoptotic transcription factor STAT1/pSTAT1 were found in lung samples from GR(dim/dim) mice. Lungs of GR(dim/dim) mice revealed apoptosis, most likely as consequence of reduced expression of the lung-protective Angpt1 compared to GR(+/+) after HS. RNA-sequencing revealed increased expression of pro-apoptotic and cytokine-signaling associated genes in lung tissue of GR(dim/dim) mice. Furthermore, high levels of pro-inflammatory cytokines and iNOS were found in lungs of GR(dim/dim) mice. Our results indicate impaired repression of STAT1/pSTAT1 due to dysfunctional GR signaling in GR(dim/dim) mice, which leads to increased inflammation and apoptosis in the lungs. These data highlight the crucial role of functional GR signaling to attenuate HS-induced lung damage. 2021 Dec eng Cells 11 *glucocorticoid receptor, *hemorrhagic shock, *homodimer, *resuscitation Jonathan M. Preuss Ute Burret Michael Gröger Sandra Kress Angelika Scheuerle Peter Möller Jan P. Tuckermann Martin Wepler Sabine Vettorazzi article Cherifi2021 Inhibition of sphingosine 1-phosphate protects mice against chondrocyte catabolism and osteoarthritis. Cartilage loss observed in osteoarthritis (OA) is prevented when osteoclasts in the subchondral bone are inhibited in mice. Here, we investigated the role of the osteoclast secretome and of the lipid mediator sphingosine 1-phosphate (S1P) in chondrocyte metabolism and OA. We used SphK1 and wild type mice to assess the effect of murine osteoclast secretome in chondrocyte metabolism. Gene and protein expressions of matrix metalloproteinase (Mmp) were quantified in chondrocytes and explants by RT-qPCR and Western blots. SphK1 mice or wild type mice treated with S1P receptor inhibitor JTE013 or anti-S1P neutralizing antibody sphingomab are analyzed by OA score and immunohistochemistry. The osteoclast secretome increased the expression of Mmp3 and Mmp13 in murine chondrocytes and cartilage explants and activated the JNK signaling pathway, which led to matrix degradation. JTE013 reversed the osteoclast-mediated chondrocyte catabolism and protected mice against OA, suggesting that osteoclastic S1P contributes to cartilage damage in OA via S1P/S1P signaling. The activity of sphingosine kinase 1 (SphK1) increased with osteoclast differentiation, and its expression was enhanced in subchondral bone of mice with OA. The expression of Mmp3 and Mmp13 in chondrocytes was low upon stimulation with the secretome of Sphk1-lacking osteoclasts. Cartilage damage was significantly reduced in SphK1 mice, but not the synovial inflammation. Finally, intra-articular administration of sphingomab inhibited the cartilage damage and synovial inflammation. Lack of S1P in myeloid cells and local S1P neutralization alleviates from osteoarthritis in mice. These data identify S1P as a therapeutic target in OA. 2021 sep 1522-9653 10.1016/j.joca.2021.06.001 Osteoarthritis and cartilage 29 1335--1345 Animals; Chondrocytes, metabolism; Lysophospholipids, antagonists & inhibitors; Male; Mice; Osteoarthritis, metabolism, prevention & control; Osteoclasts, metabolism; Secretome, metabolism; Sphingosine, analogs & derivatives, antagonists & inhibitors; Bone; Cartilage; Metalloproteinase; Osteoarthritis; Sphingosine 1 phosphate C. Cherifi A. Latourte S. Vettorazzi J. Tuckermann S. Provot H.-K. Ea A. Ledoux J. Casas O. Cuvillier P. Richette A. Ostertag E. Hay M. Cohen-Solal article Lee2021a Leukemia inhibitory factor treatment attenuates the detrimental effects of glucocorticoids on bone in mice. Glucocorticoids (GCs) are widely used drugs for the treatment of inflammatory and autoimmune diseases. However, a severe side effect induced by long-term GC therapy is osteoporosis. Leukemia inhibitory factor (LIF) - a glycoprotein 130 (gp130) dependent cytokine and member of the interleukin-6 cytokine family - is an activator protein 1 (AP-1) target gene that may be involved in one of the mechanisms underlying GC-induced bone loss. Indeed, we previously reported that the mRNA expression level of LIF was enhanced upon osteogenic differentiation, but was significantly decreased in GC-treated osteoblasts. In this study, we show that in vitro LIF treatment rescues the decreased early osteogenic differentiation and mineralization of GC-treated osteoblasts. Furthermore, we also demonstrate that in vivo LIF treatment protects against GC-mediated trabecular bone loss by decreasing the loss of both trabecular bone formation and osteoblast numbers. This protection appears to be conferred by LIF rescuing GC decreased activity of Stat3, MAPK, and Akt signaling pathways. Thus, the specific targeting of LIF signaling may represent a new therapeutic strategy to prevent GC-induced trabecular bone loss. 2021 apr 1873-2763 10.1016/j.bone.2021.115843 Bone 145 115843 Animals; Cell Differentiation; Glucocorticoids, toxicity; Leukemia Inhibitory Factor; Mice; Osteoblasts; Osteogenesis; Glucocorticoid-induced osteoporosis; Glucocorticoids; Leukemia inhibitory factor; Osteoblast differentiation Sooyeon Lee Peng Liu Mubashir Ahmad Jan P. Tuckermann article Multiplex Fluorescent Bead-Based Immunoassay for the Detection of Cytokines, Chemokines, and Growth Factors 2021 Methods Mol Biol. 2261 247-262 J. M. Preuss U. Burret S. Vettorazzi article Liao2021 Osteoblast-specific inactivation of p53 results in locally increased bone formation. Inactivation of the tumor suppressor p53 (encoded by the Trp53 gene) is relevant for development and growth of different cancers, including osteosarcoma, a primary bone tumor mostly affecting children and young adolescents. We have previously shown that deficiency of the ribosomal S6 kinase 2 (Rsk2) limits osteosarcoma growth in a transgenic mouse model overexpressing the proto-oncogene c-Fos. Our initial aim for the present study was to address the question, if Rsk2 deficiency would also influence osteosarcoma growth in another mouse model. For that purpose, we took advantage of Trp53fl/fl mice, which were crossed with Runx2Cre transgenic mice in order to inactivate p53 specifically in osteoblast lineage cells. However, since we unexpectedly identified Runx2Cre-mediated recombination also in the thymus, the majority of 6-month-old Trp53fl/fl;Runx2-Cre (thereafter termed Trp53Cre) animals displayed thymic lymphomas, similar to what has been described for Trp53-deficient mice. Since we did not detect osteosarcoma formation at that age, we could not follow our initial aim, but we studied the skeletal phenotype of Trp53Cre mice, with or without additional Rsk2 deficiency. Here we unexpectedly observed that Trp53Cre mice display a unique accumulation of trabecular bone in the midshaft region of the femur and the humerus, consistent with its previously established role as a negative regulator of osteoblastogenesis. Since this local bone mass increase in Trp53Cre mice was significantly reduced by Rsk2 deficiency, we isolated bone marrow cells from the different groups of mice and analyzed their behavior ex vivo. Here we observed a remarkable increase of colony formation, osteogenic differentiation and proliferation in Trp53Cre cultures, which was unaffected by Rsk2 deficiency. Our data thereby confirm a critical and tumorigenesis-independent function of p53 as a key regulator of mesenchymal cell differentiation. 2021 eng PloS one 16 e0249894 Animals, Bone Neoplasms/genetics/*metabolism/pathology, Bone and Bones/metabolism/*pathology, Cancellous Bone/pathology, Carcinogenesis/genetics, Cell Proliferation, Lymphoma/genetics/*metabolism/pathology, Mice, Knockout, Osteoblasts/*metabolism, Osteogenesis/*physiology, Osteosarcoma/genetics/metabolism/pathology, Thymus Neoplasms/genetics/*metabolism/pathology, Tumor Suppressor Protein p53/genetics/*metabolism Nannan Liao Till Koehne Jan Tuckermann Ioanna Triviai Michael Amling Jean-Pierre David Thorsten Schinke Julia Luther article Impact of downstream effects of glucocorticoid receptor dysfunction on organ function in critical illness-associated systemic inflammation 2020 12 18 Intensive Care Med Exp. 8 37 1 M. Wepler J. M. Preuss T. Merz O. McCook P. Radermacher J. P. Tuckermann S. Vettorazzi article Inhibition of 11β-HSD1 Expression by Insulin in Skin: Impact for Diabetic Wound Healing 2020 11 28 J Clin Med. 9 3878 12 Christina B Brazel A. Saalbach article Massive Osteopetrosis Caused by Non-Functional Osteoclasts in R51Q SNX10 Mutant Mice 2020 07 Bone 136 115360 M. Stein M. Barnea-Zohar M. Shalev E. Arman O. Brenner S. Winograd-Katz J. Gerstung F. Thalji M. Kanaan H. Elinav P. Stepensky B. Geiger J. Tuckermann A. Elson article HildebrandtBTTHR2018 Glucocorticoids suppress Wnt16 expression in osteoblasts in vitro and in vivo 2020 6 4 Sci Rep. 10 9344 1 S. Hildebrandt U. Baschant S. Thiele J. Tuckermann L.C. Hofbauer M. Rauner article PPARδ-mediated Mitochondrial Rewiring of Osteoblasts Determines Bone Mass 2020 05 21 Sci Rep. 10 8428 1 D. I H Müller C. Stoll K. Palumbo-Zerr C. Böhm B. Krishnacoumar N. Ipseiz J. Taubmann M. Zimmermann M. Böttcher D. Mougiakakos J. Tuckermann F. Djouad G. Schett C. Scholtysek G. Krönke article The Role of Glucocorticoid Receptor and Oxytocin Receptor in the Septic Heart in a Clinically Relevant, Resuscitated Porcine Model With Underlying Atherosclerosis 2020 05 14 Front Endocrinol (Lausanne) 11 299 T. Merz N. Denoix D. Wigger C. Waller M. Wepler S. Vettorazzi J. Tuckermann P. Radermacher O. McCook article Total Reflection X-ray Fluorescence Spectrometry for Trace Determination of Iron and Some Additional Elements in Biological Samples 2020 04 26 Anal Bioanal Chem. A. Gruber R. Müller A. Wagner S. Colucci M. Vujić Spasić K. Leopold article CD163 Expression Defines Specific, IRF8-dependent, Immune-Modulatory Macrophages in the Bone Marrow 2020 03 19 J Allergy Clin Immunol S0091-6749 30344-4 20 L. Fischer-Riepe N. Daber J. Schulte-Schrepping Bruna Caroline Véras De Carvalho A. Russo M. Pohlen J. Fischer A. I. Chasan M. Wolf T. Ulas S. Glander C. Schulz B. Skryabin A. Dipl. Ing. Wollbrink N. Steingraeber C. Stremmel M. Koehle F. Gärtner Sabine Vettorazzi D. Holzinger J. Gross F. Rosenbauer M. Stoll S. Niemann J. Tuckermann Joachim L. Schultze J. Roth K. Barczyk-Kahlert article Macrophage-HFE Controls Iron Metabolism and Immune Responses in Aged Mice 2020 02 20 Haematologica haematol.2019. 235630 Naveen Kumar Tangudu D. Yilmaz K. Wörle A. Gruber S. Colucci K. Leopold M. U. Muckenthaler M. Vujić Spasić article Impaired Glucocorticoid Receptor Dimerization Aggravates LPS-Induced Circulatory and Pulmonary Dysfunction 2020 01 23 Front Immunol. 10 3152 M. Wepler J. M. Preuss T. Merz C. Hartmann U. Wachter O. McCook J. Vogt S. Kress M. Gröger M. Fink A. Scheuerle P. Möller E. Calzia U. Burret P. Radermacher J. P. Tuckermann S. Vettorazzi article Brazel2020 Inhibition of 11β-HSD1 Expression by Insulin in Skin: Impact for Diabetic Wound Healing. Chronic, non-healing wounds impose a great burden on patients, professionals and health care systems worldwide. Diabetes mellitus (DM) and obesity are globally highly prevalent metabolic disorders and increase the risk for developing chronic wounds. Glucocorticoids (GCs) are endogenous stress hormones that exert profound effects on inflammation and repair systems. 11-beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) is the key enzyme which controls local GC availability in target tissues such as skin. Since treatment with GCs has detrimental side effects on skin integrity, causing atrophy and delayed wound healing, we asked whether the dysregulated expression of 11β-HSD1 and consequently local GC levels in skin contribute to delayed wound healing in obese, diabetic db/db mice. We found increased expression of 11β-HSD1 during disturbed wound healing and in the healthy skin of obese, diabetic db/db mice. Cell analysis revealed increased expression of 11β-HSD1 in fibroblasts, myeloid cells and dermal white adipose tissue from db/db mice, while expression in keratinocytes was unaffected. Among diabetes- and obesity-related factors, insulin and insulin-like growth factor 1 down-regulated 11β-HSD1 expression in fibroblasts and myeloid cells, while glucose, fatty acids, TNF-α and IL-1β did not affect it. Insulin exerted its inhibitory effect on 11β-HSD1 expression by activating PI3-kinase/Akt-signalling. Consequently, the inhibitory effect of insulin is attenuated in fibroblasts from insulin-resistant db/db mice. We conclude that insulin resistance in obesity and diabetes prevents the down-regulation of 11β-HSD1, leading to elevated endogenous GC levels in diabetic skin, which could contribute to impaired wound healing in patients with DM. 2020 nov 2077-0383 10.3390/jcm9123878 Journal of clinical medicine 9 11-beta-hydroxysteroid dehydrogenase; corticosterone; diabetes mellitus; fibroblasts; insulin; obesity; skin; wound healing Christina B. Brazel Jan C. Simon Jan P. Tuckermann Anja Saalbach article FischerRiepe2020 CD163 expression defines specific, IRF8-dependent, immune-modulatory macrophages in the bone marrow. Scavenger receptor CD163 is exclusively expressed on monocytes/macrophages and is widely used as a marker for alternatively activated macrophages. However, the role of CD163 is not yet clear. We sought to examine the function of CD163 in steady-state as well as in sterile and infectious inflammation. Expression of CD163 was analyzed under normal and inflammatory conditions in mice. Functional relevance of CD163 was investigated in models of inflammation in wild-type and CD163 mice. We describe a subpopulation of bone marrow-resident macrophages (BMRMs) characterized by a high expression of CD163 and functionally distinct from classical bone marrow-derived macrophages. Development of CD163 BMRMs is strictly dependent on IFN regulatory factor-8. CD163 BMRMs show a specific transcriptome and cytokine secretion pattern demonstrating a specific immunomodulatory profile of these cells. Accordingly, CD163 mice show a stronger inflammation in allergic contact dermatitis, indicating a regulatory role of CD163. However, CD163 mice are highly susceptible to S aureus infections, demonstrating the relevance of CD163 for antimicrobial defense as well. Our data indicate that anti-inflammatory and immunosuppressive mechanisms are not necessarily associated with a decreased antimicrobial activity. In contrast, our data define a novel macrophage population that controls overwhelming inflammation on one hand but is also necessary for an effective control of infections on the other hand. 2020 nov 1097-6825 10.1016/j.jaci.2020.02.034 The Journal of allergy and clinical immunology 146 1137--1151 Animals; Antigens, CD, genetics, metabolism; Antigens, Differentiation, Myelomonocytic, genetics, metabolism; Bone Marrow Cells, immunology, metabolism; Cells, Cultured; Cytokines, metabolism; Dermatitis, Allergic Contact, immunology; Disease Models, Animal; Disease Susceptibility; Humans; Immunomodulation; Inflammation, immunology; Interferon Regulatory Factors, genetics, metabolism; Macrophage Activation; Macrophages, immunology, metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Receptors, Cell Surface, genetics, metabolism; Staphylococcal Infections, immunology; Staphylococcus aureus, physiology; Transcriptome; IFN regulatory factor 8; Resident bone marrow macrophages; scavenger receptor CD163; sterile and systemic inflammation Lena Fischer-Riepe Niklas Daber Jonas Schulte-Schrepping Bruna Caroline Véras De Carvalho Antonella Russo Michele Pohlen Josephine Fischer Achmet Imam Chasan Marc Wolf Thomas Ulas Shirin Glander Christian Schulz Boris Skryabin Andreas Wollbrink Dipl-Ing Nadine Steingraeber Christopher Stremmel Megan Koehle Florian Gärtner Sabine Vettorazzi Dirk Holzinger Joachim Gross Frank Rosenbauer Monika Stoll Silke Niemann Jan Tuckermann Joachim L. Schultze Johannes Roth Katarzyna Barczyk-Kahlert article Hachemi2020 Intact Glucocorticoid Receptor Dimerization Is Deleterious in Trauma-Induced Impaired Fracture Healing. Following severe trauma, fracture healing is impaired because of overwhelming systemic and local inflammation. Glucocorticoids (GCs), acting the glucocorticoid receptor (GR), influence fracture healing by modulating the trauma-induced immune response. GR dimerization-dependent gene regulation is essential for the anti-inflammatory effects of GCs. Therefore, we investigated in a murine trauma model of combined femur fracture and thoracic trauma, whether effective GR dimerization influences the pathomechanisms of trauma-induced compromised fracture healing. To this end, we used mice with decreased GR dimerization ability (GR ). The healing process was analyzed by cytokine/chemokine multiplex analysis, flow cytometry, gene-expression analysis, histomorphometry, micro-computed tomography, and biomechanical testing. GR mice did not display a systemic or local hyper-inflammation upon combined fracture and thorax trauma. Strikingly, we discovered that GR mice were protected from fracture healing impairment induced by the additional thorax trauma. Collectively and in contrast to previous studies describing the beneficial effects of intact GR dimerization in inflammatory models, we report here an adverse role of intact GR dimerization in trauma-induced compromised fracture healing. 2020 1664-3224 10.3389/fimmu.2020.628287 Frontiers in immunology 11 628287 Animals; Fracture Healing, genetics, immunology; Male; Mice; Mice, Transgenic; Protein Multimerization, genetics, immunology; Receptors, Glucocorticoid, genetics, immunology; Thoracic Injuries, genetics, immunology, pathology; bone repair; fracture; glucocorticoid receptor; inflammation; thoracic trauma Yasmine Hachemi Anna E. Rapp Sooyeon Lee Ann-Kristin Dorn Benjamin T. Krüger Kathrin Kaiser Anita Ignatius Jan Tuckermann article Merz2020 The Role of Glucocorticoid Receptor and Oxytocin Receptor in the Septic Heart in a Clinically Relevant, Resuscitated Porcine Model With Underlying Atherosclerosis. The pathophysiology of sepsis-induced myocardial dysfunction is not resolved to date and comprises inflammation, barrier dysfunction and oxidative stress. Disease-associated reduction of tissue cystathionine-γ-lyase (CSE) expression, an endogenous H S-producing enzyme, is associated with oxidative stress, barrier dysfunction and organ injury. CSE-mediated cardio-protection has been suggested to be related the upregulation of oxytocin receptor (OTR). CSE can also mediate glucocorticoid receptor (GR) signaling, which is important for normal heart function. A sepsis-related loss of cardiac CSE expression associated with impaired organ function has been reported previously. The aim of this current study was to investigate the role of cardiac GR and OTR after polymicrobial sepsis in a clinically relevant, resuscitated, atherosclerotic porcine model. Anesthetized and instrumented FBM (Familial Hypercholesterolemia Bretoncelles Meishan) pigs with high fat diet-induced atherosclerosis underwent poly-microbial septic shock ( = 8) or sham procedure ( = 5), and subsequently received intensive care therapy with fluid and noradrenaline administration for 24 h. Cardiac protein expression and mRNA levels were analyzed. Systemic troponin, a marker of cardiac injury, was significantly increased in septic animals in contrast to sham, whereas OTR and GR expression in septic hearts were reduced, along with a down-regulation of anti-inflammatory GR target genes and the antioxidant transcription factor NRF2. These results suggest a potential interplay between GR, CSE, and OTR in sepsis-mediated oxidative stress, inflammation and cardiac dysfunction. 2020 1664-2392 10.3389/fendo.2020.00299 Frontiers in endocrinology 11 299 Animals; Atherosclerosis, physiopathology; Cystathionine gamma-Lyase, genetics, metabolism; Disease Models, Animal; Gene Expression Regulation; Heart Diseases, etiology, metabolism, pathology; Hydrogen Sulfide, metabolism; Hypercholesterolemia, physiopathology; Male; Oxidative Stress; Receptors, Glucocorticoid, genetics, metabolism; Receptors, Oxytocin, genetics, metabolism; Shock, Septic, complications; Signal Transduction; Swine; cystathionine-γ-lyase; glucocorticoid receptor; heart; inflammation; oxidative stress; oxytocin receptor; sepsis Tamara Merz Nicole Denoix Daniela Wigger Christiane Waller Martin Wepler Sabine Vettorazzi Jan Tuckermann Peter Radermacher Oscar McCook article Hildebrandt2020 Author Correction: Glucocorticoids suppress Wnt16 expression in osteoblasts in vitro and in vivo. An amendment to this paper has been published and can be accessed via a link at the top of the paper. 2020 jun 2045-2322 10.1038/s41598-020-65962-6 Scientific reports 10 9344 Susanne Hildebrandt Ulrike Baschant Sylvia Thiele Jan Tuckermann Lorenz C. Hofbauer Martina Rauner article Mueller2020 PPARδ-mediated mitochondrial rewiring of osteoblasts determines bone mass. Bone turnover, which is determined by osteoclast-mediated bone resorption and osteoblast-mediated bone formation, represents a highly energy consuming process. The metabolic requirements of osteoblast differentiation and mineralization, both essential for regular bone formation, however, remain incompletely understood. Here we identify the nuclear receptor peroxisome proliferator-activated receptor (PPAR) δ as key regulator of osteoblast metabolism. Induction of PPARδ was essential for the metabolic adaption and increased rate in mitochondrial respiration necessary for the differentiation and mineralization of osteoblasts. Osteoblast-specific deletion of PPARδ in mice, in turn, resulted in an altered energy homeostasis of osteoblasts, impaired mineralization and reduced bone mass. These data show that PPARδ acts as key regulator of osteoblast metabolism and highlight the relevance of cellular metabolic rewiring during osteoblast-mediated bone formation and bone-turnover. 2020 may 2045-2322 10.1038/s41598-020-65305-5 Scientific reports 10 8428 Animals; Bone Density, physiology; Bone Remodeling, physiology; Cell Differentiation; Cells, Cultured; Energy Metabolism, genetics, physiology; Mesenchymal Stem Cells, cytology; Mice; Mice, Knockout; Mitochondria, metabolism; Osteoblasts, cytology, metabolism; Osteoclasts, metabolism; Osteogenesis, physiology; Oxidative Phosphorylation; PPAR delta, genetics, metabolism Dorothea I. H. Müller Cornelia Stoll Katrin Palumbo-Zerr Christina Böhm Brenda Krishnacoumar Natacha Ipseiz Jule Taubmann Max Zimmermann Martin Böttcher Dimitrios Mougiakakos Jan Tuckermann Farida Djouad Georg Schett Carina Scholtysek Gerhard Krönke article Effects of sodium thiosulfate (Na2S2O3) during resuscitation from hemorrhagic shock in swine with preexisting atherosclerosis 2020 01 Pharmacol Res. 151 104536 T. Datzmann A. Hoffmann O. McCook T. Merz U. Wachter J. Preuss S. Vettorazzi E. Calzia M. Gröger F. Kohn A. Schmid N. Denoix P. Radermacher M. Wepler article Stein2020 Massive osteopetrosis caused by non-functional osteoclasts in R51Q SNX10 mutant mice. The R51Q mutation in sorting nexin 10 (SNX10) was shown to cause a lethal genetic disease in humans, namely autosomal recessive osteopetrosis (ARO). We describe here the first R51Q SNX10 knock-in mouse model and show that mice homozygous for this mutation exhibit massive, early-onset, and widespread osteopetrosis. The mutant mice exhibit multiple additional characteristics of the corresponding human disease, including stunted growth, failure to thrive, missing or impacted teeth, occasional osteomyelitis, and a significantly-reduced lifespan. Osteopetrosis in this model is the result of osteoclast inactivity that, in turn, is caused by absence of ruffled borders in the mutant osteoclasts and by their inability to secrete protons. These results confirm that the R51Q mutation in SNX10 is a causative factor in ARO and provide a model system for studying this rare disease. 2020 jul 1873-2763 10.1016/j.bone.2020.115360 Bone 136 115360 Animals; Mice; Mutation, genetics; Osteoclasts; Osteopetrosis, diagnostic imaging, genetics; Sorting Nexins, genetics; Autosomal recessive osteopetrosis; Osteoclast; Osteopetrosis; SNX10; Sorting nexin 10 Merle Stein Maayan Barnea-Zohar Moran Shalev Esther Arman Ori Brenner Sabina Winograd-Katz Jennifer Gerstung Fadi Thalji Moien Kanaan Hila Elinav Polina Stepensky Benjamin Geiger Jan Tuckermann Ari Elson article Wepler2020 Impact of downstream effects of glucocorticoid receptor dysfunction on organ function in critical illness-associated systemic inflammation. Glucocorticoids (GCs) are stress hormones that regulate developmental and physiological processes and are among the most potent anti-inflammatory drugs to suppress chronic and acute inflammation. GCs act through the glucocorticoid receptor (GR), a ubiquitously expressed ligand-activated transcription factor, which translocates into the nucleus and can act via two different modes, as a GR monomer or as a GR dimer. These two modes of action are not clearly differentiated in practice and may lead to completely different therapeutic outcomes. Detailed aspects of GR mechanisms are often not taken into account when GCs are used in different clinical scenarios. Patients, with critical illness-related corticosteroid insufficiency, treated with natural or synthetic GCs are still missing a clearly defined therapeutic strategy. This review discusses the different modes of GR function and its importance on organ function in vivo. 2020 dec 2197-425X 10.1186/s40635-020-00325-z Intensive care medicine experimental 8 37 Dimer; Dysfunction; Glucocorticoid receptor; Monomer; Mouse models; Organ function; Systemic inflammation Martin Wepler Jonathan M. Preuss Tamara Merz Oscar McCook Peter Radermacher Jan P. Tuckermann Sabine Vettorazzi article Glucocorticoids employ the monomeric glucocorticoid receptor to potentiate vitamin D3 and parathyroid hormone-induced osteoclastogenesis 2019 12 FASEB J. 33 14394-14409 12 H. H. Conaway P. Henning A. Lie J. Tuckermann U. H. Lerner article A Jack of All Trades: Impact of Glucocorticoids on Cellular Cross-Talk in Osteoimmunology 2019 10 17 Front Immunol. 10 2460 M. Ahmad Y. Hachemi K. Paxian F. Mengele M. Koenen J. Tuckermann article mir-124-5p Regulates Phagocytosis of Human Macrophages by Targeting the Actin Cytoskeleton via the ARP2/3 Complex 2019 10 04 Front Immunol. 2210 10 E. Herdoiza Padilla P. Crauwels T. Bergner N. Wiederspohn S. Förstner R. Rinas A. Ruf M. Kleemann R. Handrick J. Tuckermann K. Otte P. Walther CU. Riedel article RNAi-Screening in Knochenbildenden Zellen 2019 09 03 BIOspektrum T. Kroll M. Ahmad A. Ploubidou J. Tuckermann article Fighting the Fire: Mechanisms of Inflammatory Gene Regulation by the Glucocorticoid Receptor 2019 08 07 Front Immunol. 1859 10 L. Escoter-Torres G. Caratti A. Mechtidou J. Tuckermann N. H. Uhlenhaut S. Vettorazzi article Despite Genetic Iron Overload, Hfe-Hemochromatosis Mice Do Not Show Bone Loss 2019 07 26 JBMR Plus 3 e10206 9 A. Wagner B. Alan D. Yilmaz M. Ahmad P. Liu NK. Tangudu J. P. Tuckermann M. Vujić Spasić article Osteoblast-derived NOTUM reduces cortical bone mass in mice and the NOTUM locus is associated with bone mineral density in humans 2019 07 15 FASEB J. 33 11163-11179 10 S. Movérare-Skrtic KH. Nilsson P. Henning T. Funck-Brentano M. Nethander F. Rivadeneira G. Coletto Nunes A. Koskela J. Tuukkanen J. Tuckermann C. Perret PPC. Souza U. H. Lerner C. Ohlsson article PfanderFBLV2019 Cdk5 Deletion Enhances the Anti-inflammatory Potential of GC-Mediated GR Activation During Inflammation 2019 7 10 Front. Immunol. 10 1554 10 P. Pfänder Miray Fidan U. Burret Lena Lipinski Sabine Vettorazzi article Glucocorticoids Shape Macrophage Phenotype for Tissue Repair 2019 07 09 Front Immunol. 1591 10 T. Desgeorges G. Caratti R. Mounier J. Tuckermann B. Chazaud article vanWeertBSVMHPZSRTSM2019 Identification of mineralocorticoid receptor target genes in the mouse hippocampus 2019 5 23 J Neuroendocrinol. e12735 8 LTCM. van Weert JC. Buurstede HCM. Sips S. Vettorazzi IM. Mol J. Hartmann S. Prekovic W. Zwart MV. Schmidt B. Roozendaal JP. Tuckermann RA. Sarabdjitsingh OC. Meijer article TanguduBSCS2019 Deregulation of Hepatic Mek1/2⁻Erk1/2 Signaling Module in Iron Overload Conditions 2019 5 7 Pharmaceuticals (Basel) 7 2 12 NK. Tangudu N. Buth P. Strnad IC. Cirstea MV. Spasic´ article GlantschnigKGKPWPCGHVBTUHS2019 A miR-29a-driven negative feedback loop regulates peripheral glucocorticoid receptor signaling 2019 2 11 FASEB J. 33 5924-5941 5 C. Glantschnig M. Koenen M. Gil-Lozano M. Karbiener I. Pickrahn J. Williams-Dautovich R. Patel CL. Cummins M. Giroud G. Hartleben E. Vogl M. Blüher J. Tuckermann H. Uhlenhaut S. Herzig M. Scheideler article RothWWSASBSBTE2019 Phosphorylation of the phosphatase PTPROt at Tyr399 is a molecular switch that controls osteoclast activity and bone mass in vivo 2019 1 8 Sci Signal 8 563 12 L. Roth J. Wakim E. Wasserman M. Shalev E. Arman M. Stein V. Brumfeld CA. Sagum MT. Bedford J. Tuckermann A. Elson article MoverareSkrtic2019 Osteoblast-derived NOTUM reduces cortical bone mass in mice and the , javax.xml.bind.JAXBElement@5166fe8c, locus is associated with bone mineral density in humans. Osteoporosis is a common skeletal disease, affecting millions of individuals worldwide. Currently used osteoporosis treatments substantially reduce vertebral fracture risk, whereas nonvertebral fracture risk, mainly caused by reduced cortical bone mass, has only moderately been improved by the osteoporosis drugs used, defining an unmet medical need. Because several wingless-type MMTV integration site family members (WNTs) and modulators of WNT activity are major regulators of bone mass, we hypothesized that NOTUM, a secreted WNT lipase, might modulate bone mass an inhibition of WNT activity. To characterize the possible role of endogenous NOTUM as a physiologic modulator of bone mass, we developed global, cell-specific, and inducible -inactivated mouse models. expression was high in the cortical bone in mice, and conditional inactivation revealed that osteoblast lineage cells are the principal source of NOTUM in the cortical bone. Osteoblast lineage-specific inactivation increased cortical bone thickness an increased periosteal circumference. Inducible inactivation in adult mice increased cortical bone thickness as a result of increased periosteal bone formation, and silencing of expression in cultured osteoblasts enhanced osteoblast differentiation. Large-scale human genetic analyses identified genetic variants mapping to the locus that are strongly associated with bone mineral density (BMD) as estimated with quantitative ultrasound in the heel. Thus, osteoblast-derived NOTUM is an essential local physiologic regulator of cortical bone mass effects on periosteal bone formation in adult mice, and genetic variants in the locus are associated with BMD variation in adult humans. Therapies targeting osteoblast-derived NOTUM may prevent nonvertebral fractures.-Movérare-Skrtic, S., Nilsson, K. H., Henning, P., Funck-Brentano, T., Nethander, M., Rivadeneira, F., Coletto Nunes, G., Koskela, A., Tuukkanen, J., Tuckermann, J., Perret, C., Souza, P. P. C., Lerner, U. H., Ohlsson, C. Osteoblast-derived NOTUM reduces cortical bone mass in mice and the locus is associated with bone mineral density in humans. 2019 oct 1530-6860 10.1096/fj.201900707R FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 11163--11179 Animals; Bone Density, genetics, physiology; Cell Differentiation, genetics, physiology; Cortical Bone, metabolism, physiology; Esterases, genetics, metabolism; Female; Fractures, Bone, metabolism, physiopathology; Genetic Variation, genetics; Humans; Male; Mice; Osteoblasts, metabolism; Osteogenesis, genetics, physiology; Osteoporosis, metabolism, physiopathology; Wnt Proteins, metabolism; WNT16; osteoporosis; transgenic Sofia Movérare-Skrtic Karin H. Nilsson Petra Henning Thomas Funck-Brentano Maria Nethander Fernando Rivadeneira Glaucia Coletto Nunes Antti Koskela Juha Tuukkanen Jan Tuckermann Christine Perret Pedro Paulo Chaves Souza Ulf H. Lerner Claes Ohlsson article HerdoizaPadilla2019 mir-124-5p Regulates Phagocytosis of Human Macrophages by Targeting the Actin Cytoskeleton via the ARP2/3 Complex. Phagocytosis is a cellular process crucial for recognition and removal of apoptotic cells and foreign particles, subsequently initiating appropriate immune responses. The process of phagocytosis is highly complex and involves major rearrangements of the cytoskeleton. Due to its complexity and importance for tissue homoeostasis and immune responses, it is tightly regulated. Over the last decade, microRNAs (miRNAs) have emerged as important regulators of biological pathways including the immune response by fine-tuning expression of gene regulatory networks. In order to identify miRNAs implicated in the regulation of phagocytosis, a systematic screening of all currently known, human miRNAs was performed using THP-1 macrophage-like cells and serum-opsonized latex beads. Of the total of 2,566 miRNAs analyzed, several led to significant changes in phagocytosis. Among these, we validated miR-124-5p as a novel regulator of phagocytosis. Transfection with miR-124-5p mimics reduced the number of phagocytic cells as well as the phagocytic activity of phorbol-12-myristate-13-acetate (PMA)-activated THP-1 cells and differentiated primary human macrophages. analysis suggested that miR-124-5p targets genes involved in regulation of the actin cytoskeleton. Transcriptional analyses revealed that expression of genes encoding for several subunits of the ARP2/3 complex, a crucial regulator of actin polymerization, is reduced upon transfection of cells with miR-124-5p. Further analyses identified potential binding motifs for miR-124-5p in the mRNAs of these genes. Luciferase reporter assays using these binding motifs indicate that at least two of the genes ( and ) are direct targets of miR-124-5p. Moreover, ARPC3 and ARPC4 protein levels were significantly reduced following miR-124-5p transfection. Collectively, the presented results suggest that miR-124-5p regulates phagocytosis in human macrophages by directly targeting expression of components of the ARP2/3 complex. 2019 1664-3224 10.3389/fimmu.2019.02210 Frontiers in immunology 10 2210 Actin Cytoskeleton, physiology; Actin-Related Protein 2-3 Complex, physiology; HEK293 Cells; Humans; Macrophages, immunology; MicroRNAs, physiology; Phagocytosis; THP-1 Cells; ARP2/3; high-content screening; macrophage; microRNA; phagocytosis Estefania Herdoiza Padilla Peter Crauwels Tim Bergner Nicole Wiederspohn Sabrina Förstner Rebecca Rinas Anna Ruf Michael Kleemann René Handrick Jan Tuckermann Kerstin Otte Paul Walther Christian U. Riedel article Javaheri2019 Retraction Note: Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation. An amendment to this paper has been published and can be accessed via a link at the top of the paper. 2019 aug 2041-4889 10.1038/s41419-019-1853-1 Cell death & disease 10 605 Tahereh Javaheri Zahra Kazemi Jan Pencik Ha T. T. Pham Maximilian Kauer Rahil Noorizadeh Barbara Sax Harini Nivarthi Michaela Schlederer Barbara Maurer Maximillian Hofbauer Dave N. T. Aryee Marc Wiedner Eleni M. Tomazou Malcolm Logan Christine Hartmann Jan P. Tuckermann Lukas Kenner Mario Mikula Helmut Dolznig Aykut Üren Günther H. Richter Florian Grebien Heinrich Kovar Richard Moriggl article Tangudu2019 Deregulation of Hepatic Mek1/2⁻Erk1/2 Signaling Module in Iron Overload Conditions. The liver, through the production of iron hormone hepcidin, controls body iron levels. High liver iron levels and deregulated hepcidin expression are commonly observed in many liver diseases including highly prevalent genetic iron overload disorders. In spite of a number of breakthrough investigations into the signals that control hepcidin expression, little progress has been made towards investigations into intracellular signaling in the liver under excess of iron. This study examined hepatic signaling pathways underlying acquired and genetic iron overload conditions. Our data demonstrate that hepatic iron overload associates with a decline in the activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) kinase (Mek1/2) pathway by selectively affecting the phosphorylation of Erk1/2. We propose that Mek1/2-Erk1/2 signaling is uncoupled from iron-Bmp-Smad-mediated hepcidin induction and that it may contribute to a number of liver pathologies in addition to toxic effects of iron. We believe that our findings will advance the understanding of cellular signaling events in the liver during iron overload of different etiologies. 2019 may 1424-8247 10.3390/ph12020070 Pharmaceuticals (Basel, Switzerland) 12 Bmp/Smad; Hfe; Mek/Erk; hepcidin; iron; liver Naveen Kumar Tangudu Nils Buth Pavel Strnad Ion C. Cirstea Maja Vujic Spasic article Wepler2019 Impaired Glucocorticoid Receptor Dimerization Aggravates LPS-Induced Circulatory and Pulmonary Dysfunction. Sepsis, that can be modeled by LPS injections, as an acute systemic inflammation syndrome is the most common cause for acute lung injury (ALI). ALI induces acute respiratory failure leading to hypoxemia, which is often associated with multiple organ failure (MOF). During systemic inflammation, the hypothalamus-pituitary-adrenal axis (HPA) is activated and anti-inflammatory acting glucocorticoids (GCs) are released to overcome the inflammation. GCs activate the GC receptor (GR), which mediates its effects via a GR monomer or GR dimer. The detailed molecular mechanism of the GR in different inflammatory models and target genes that might be crucial for resolving inflammation is not completely identified. We previously observed that mice with attenuated GR dimerization (GR ) had a higher mortality in a non-resuscitated lipopolysaccharide (LPS)- and cecal ligation and puncture (CLP)-induced inflammation model and are refractory to exogenous GCs to ameliorate ALI during inflammation. Therefore, we hypothesized that impaired murine GR dimerization (GR ) would further impair organ function in LPS-induced systemic inflammation under human like intensive care management and investigated genes that are crucial for lung function in this setup. Anesthetized GR and wildtype (GR ) mice were challenged with LPS (10 mg·kg , intraperitoneal) and underwent intensive care management ("lung-protective" mechanical ventilation, crystalloids, and norepinephrine) for 6 h. Lung mechanics and gas exchange were assessed together with systemic hemodynamics, acid-base status, and mitochondrial oxygen consumption (JO ). Western blots, immunohistochemistry, and real time quantitative polymerase chain reaction were performed to analyze lung tissue and inflammatory mediators were analyzed in plasma and lung tissue. When animals were challenged with LPS and subsequently resuscitated under intensive care treatment, GR mice had a higher mortality compared to GR mice, induced by an increased need of norepinephrine to achieve hemodynamic targets. After challenge with LPS, GR mice also displayed an aggravated ALI shown by a more pronounced impairment of gas exchange, lung mechanics and increased osteopontin (Opn) expression in lung tissue. Impairment of GR dimerization aggravates systemic hypotension and impairs lung function during LPS-induced endotoxic shock in mice. We demonstrate that the GR dimer is an important mediator of hemodynamic stability and lung function, possibly through regulation of Opn, during LPS-induced systemic inflammation. 2019 1664-3224 10.3389/fimmu.2019.03152 Frontiers in immunology 10 3152 Acute Lung Injury, etiology, metabolism; Animals; Dimerization; Lipopolysaccharides, toxicity; Mice; Protein Multimerization; Receptors, Glucocorticoid, chemistry, metabolism; Shock, Septic, complications, metabolism, physiopathology; endotoxic shock; glucocorticoid receptor; inflammation; lung function; osteopontin Martin Wepler Jonathan M. Preuss Tamara Merz Clair Hartmann Ulrich Wachter Oscar McCook Josef Vogt Sandra Kress Michael Gröger Marina Fink Angelika Scheuerle Peter Möller Enrico Calzia Ute Burret Peter Radermacher Jan P. Tuckermann Sabine Vettorazzi article Wagner2019 Despite Genetic Iron Overload, , javax.xml.bind.JAXBElement@e709a68, -Hemochromatosis Mice Do Not Show Bone Loss. One of the most prevalent genetic iron overload disorders in Caucasians is caused by mutations in the gene. Both patients and -mouse models develop a progressive accumulation of iron in the parenchymal cells of various tissues, eventually resulting in liver cirrhosis, hepatocellular carcinoma, cardiomyopathies, hypogonadism, and other pathologies. Clinical data and preclinical models have brought considerable attention to the correlation between iron overload and the development of osteoporosis in hemochromatosis. Our study critically challenges this concept. We show that systemic iron overload, at the degree present in mice, does not associate with the microarchitecture impairment of long bones, thus excluding a negative effect of iron overload on bone integrity. We further reveal that Hfe actions in osteoblasts and osteoclasts are dispensable for the maintenance of bone and iron homeostasis in mice under steady-state conditions. We conclude that, despite systemic iron overload, mice present normal physiological bone homeostasis. © 2019 The Authors. in published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research. 2019 sep 2473-4039 10.1002/jbm4.10206 JBMR plus 3 e10206 BONE; HFE‐HEMOCHROMATOSIS; IRON; OSTEOBLAST/OSTEOCLASTS; OSTEOPOROSIS Alessa Wagner Betül Alan Dilay Yilmaz Mubashir Ahmad Peng Liu Naveen Kumar Tangudu Jan P. Tuckermann Maja Vujic Spasic article Weert2019 Identification of mineralocorticoid receptor target genes in the mouse hippocampus. Brain mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) respond to the same glucocorticoid hormones but can have differential effects on cellular function. Several lines of evidence suggest that MR-specific target genes must exist and might underlie the distinct effects of the receptors. The present study aimed to identify MR-specific target genes in the hippocampus, a brain region where MR and GR are co-localised and play a role in the stress response. Using genome-wide binding of both receptor types, we previously identified MR-specific, MR-GR overlapping and GR-specific putative target genes. We now report altered gene expression levels of such genes in the hippocampus of forebrain MR knockout (fbMRKO) mice, killed at the time of their endogenous corticosterone peak. Of those genes associated with MR-specific binding, the most robust effect was a 50% reduction in Jun dimerization protein 2 (Jdp2) mRNA levels in fbMRKO mice. Down-regulation was also observed for the MR-specific Nitric oxide synthase 1 adaptor protein (Nos1ap) and Suv3 like RNA helicase (Supv3 l1). Interestingly, the classical glucocorticoid target gene FK506 binding protein 5 (Fkbp5), which is associated with MR and GR chromatin binding, was expressed at substantially lower levels in fbMRKO mice. Subsequently, hippocampal Jdp2 was confirmed to be up-regulated in a restraint stress model, posing Jdp2 as a bona fide MR target that is also responsive in an acute stress condition. Thus, we show that MR-selective DNA binding can reveal functional regulation of genes and further identify distinct MR-specific effector pathways. 2019 aug 1365-2826 10.1111/jne.12735 Journal of neuroendocrinology 31 e12735 Animals; Binding Sites, genetics; Female; Gene Expression Regulation; Hippocampus, metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Glucocorticoid, genetics, metabolism; Receptors, Mineralocorticoid, genetics, physiology; Jdp2 ; glucocorticoids; mineralocorticoid receptor knockout; restraint stress; transcription Lisa T. C. M. Weert Jacobus C. Buurstede Hetty C. M. Sips Sabine Vettorazzi Isabel M. Mol Jakob Hartmann Stefan Prekovic Wilbert Zwart Mathias V. Schmidt Benno Roozendaal Jan P. Tuckermann R. Angela Sarabdjitsingh Onno C. Meijer article Ahmad2019 A Jack of All Trades: Impact of Glucocorticoids on Cellular Cross-Talk in Osteoimmunology. Glucocorticoids (GCs) are known to have a strong impact on the immune system, metabolism, and bone homeostasis. While these functions have been long investigated separately in immunology, metabolism, or bone biology, the understanding of how GCs regulate the cellular cross-talk between innate immune cells, mesenchymal cells, and other stromal cells has been garnering attention rather recently. Here we review the recent findings of GC action in osteoporosis, inflammatory bone diseases (rheumatoid and osteoarthritis), and bone regeneration during fracture healing. We focus on studies of pre-clinical animal models that enable dissecting the role of GC actions in innate immune cells, stromal cells, and bone cells using conditional and function-selective mutant mice of the GC receptor (GR), or mice with impaired GC signaling. Importantly, GCs do not only directly affect cellular functions, but also influence the cross-talk between mesenchymal and immune cells, contributing to both beneficial and adverse effects of GCs. Given the importance of endogenous GCs as stress hormones and the wide prescription of pharmaceutical GCs, an improved understanding of GC action is decisive for tackling inflammatory bone diseases, osteoporosis, and aging. 2019 1664-3224 10.3389/fimmu.2019.02460 Frontiers in immunology 10 2460 Animals; Anti-Inflammatory Agents, pharmacology; Bone and Bones, drug effects, metabolism; Cell Communication, drug effects; Disease Susceptibility; Glucocorticoids, metabolism, pharmacology; Hormones, metabolism; Humans; Immune System, cytology, immunology, metabolism; Osteitis, etiology, metabolism, pathology; Osteoarthritis, etiology, metabolism, pathology; Osteocytes, metabolism; Signal Transduction; Stress, Physiological; Stromal Cells, metabolism; arthritis; conditional knockout mice; fracture healing; glucocorticoid receptor; glucocorticoids; inflammation; osteoporosis Mubashir Ahmad Yasmine Hachemi Kevin Paxian Florian Mengele Mascha Koenen Jan Tuckermann article BeeviTVD2019 Biodrug Suppresses Breast and Colorectal Cancer in Murine Models 2019 Methods Mol Biol. 1974 245-263 SS. Beevi NK. Tangudu VK. Verma L. Dinesh Kumar article Motta2019 Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling. Noonan syndrome (NS), the most common RASopathy, is caused by mutations affecting signaling through RAS and the MAPK cascade. Recently, genome scanning has discovered novel genes implicated in NS, whose function in RAS-MAPK signaling remains obscure, suggesting the existence of unrecognized circuits contributing to signal modulation in this pathway. Among these genes, leucine zipper-like transcriptional regulator 1 (LZTR1) encodes a functionally poorly characterized member of the BTB/POZ protein superfamily. Two classes of germline LZTR1 mutations underlie dominant and recessive forms of NS, while constitutional monoallelic, mostly inactivating, mutations in the same gene cause schwannomatosis, a cancer-prone disorder clinically distinct from NS. Here we show that dominant NS-causing LZTR1 mutations do not affect significantly protein stability and subcellular localization. We provide the first evidence that these mutations, but not the missense changes occurring as biallelic mutations in recessive NS, enhance stimulus-dependent RAS-MAPK signaling, which is triggered, at least in part, by an increased RAS protein pool. Moreover, we document that dominant NS-causing mutations do not perturb binding of LZTR1 to CUL3, a scaffold coordinating the assembly of a multimeric complex catalyzing protein ubiquitination but are predicted to affect the surface of the Kelch domain mediating substrate binding to the complex. Collectively, our data suggest a model in which LZTR1 contributes to the ubiquitinationof protein(s) functioning as positive modulator(s) of the RAS-MAPK signaling pathway. In this model, LZTR1 mutations are predicted to variably impair binding of these substrates to the multi-component ligase complex and their efficient ubiquitination and degradation, resulting in MAPK signaling upregulation. 2019 mar 1460-2083 10.1093/hmg/ddy412 Human molecular genetics 28 1007--1022 Cullin Proteins, metabolism; Humans; Kelch Repeat; Mitogen-Activated Protein Kinases, metabolism; Models, Molecular; Mutation; Noonan Syndrome, genetics, metabolism; Protein Binding; Protein Conformation; Protein Stability; Protein Transport; Signal Transduction; Transcription Factors, chemistry, genetics, metabolism; ras Proteins, metabolism Marialetizia Motta Miray Fidan Emanuele Bellacchio Francesca Pantaleoni Konstantin Schneider-Heieck Simona Coppola Guntram Borck Leonardo Salviati Martin Zenker Ion C. Cirstea Marco Tartaglia article EscoterTorres2019 Fighting the Fire: Mechanisms of Inflammatory Gene Regulation by the Glucocorticoid Receptor. For many decades, glucocorticoids have been widely used as the gold standard treatment for inflammatory conditions. Unfortunately, their clinical use is limited by severe adverse effects such as insulin resistance, cardiometabolic diseases, muscle and skin atrophies, osteoporosis, and depression. Glucocorticoids exert their effects by binding to the Glucocorticoid Receptor (GR), a ligand-activated transcription factor which both positively, and negatively regulates gene expression. Extensive research during the past several years has uncovered novel mechanisms by which the GR activates and represses its target genes. Genome-wide studies and mouse models have provided valuable insight into the molecular mechanisms of inflammatory gene regulation by GR. This review focusses on newly identified target genes and GR co-regulators that are important for its anti-inflammatory effects in innate immune cells, as well as mutations within the GR itself that shed light on its transcriptional activity. This research progress will hopefully serve as the basis for the development of safer immune suppressants with reduced side effect profiles. 2019 1664-3224 10.3389/fimmu.2019.01859 Frontiers in immunology 10 1859 Animals; Gene Expression Regulation, drug effects, immunology; Glucocorticoids, immunology, pharmacology; Humans; Immunosuppressive Agents, immunology, pharmacology; Receptors, Glucocorticoid, immunology; gene regulation; glucocorticoid receptor; inflammation; macrophages; mouse models Laura Escoter-Torres Giorgio Caratti Aikaterini Mechtidou Jan Tuckermann Nina Henriette Uhlenhaut Sabine Vettorazzi article Conaway2019 Glucocorticoids employ the monomeric glucocorticoid receptor to potentiate vitamin D, javax.xml.bind.JAXBElement@ee08377, and parathyroid hormone-induced osteoclastogenesis. Glucocorticoid (GC) therapy decreases bone mass and increases the risk of fractures. We investigated interactions between the GC dexamethasone (DEX) and the bone resorptive agents 1,25(OH) -vitamin D (D3) and parathyroid hormone (PTH) on osteoclastogenesis. We observed a synergistic potentiation of osteoclast progenitor cell differentiation and formation of osteoclasts when DEX was added to either D3- or PTH-treated mouse bone marrow cell (BMC) cultures. Cotreatment of DEX with D3 or PTH increased gene encoding calcitonin receptor ( ), acid phosphatase 5, tartrate resistant ( ), cathepsin K ( ), and TNF superfamily member 11 ( ) mRNA, receptor activator of NF-κB ligand protein (RANKL), numbers of osteoclasts on plastic, and pit formation and release of C-terminal fragment of type I collagen from cells cultured on bone slices. Enhanced RANKL protein expression caused by D3 and DEX was absent in BMC from mice in which the GC receptor (GR) was deleted in stromal cells/osteoblasts. Synergistic interactions between DEX and D3 on RANKL and osteoclast formation were present in BMC from mice with attenuated GR dimerization. These data demonstrate that the GR cooperates with D3 and PTH signaling, causing massive osteoclastogenesis, which may explain the rapid bone loss observed with high dosages of GC treatment.-Conaway, H. H., Henning, P., Lie, A., Tuckermann, J., Lerner, U. H. Glucocorticoids employ the monomeric glucocorticoid receptor to potentiate vitamin D and parathyroid hormone-induced osteoclastogenesis. 2019 dec 1530-6860 10.1096/fj.201802729RRR FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 14394--14409 Animals; Cholecalciferol, pharmacology; Dexamethasone, pharmacology; Drug Synergism; Gene Deletion; Gene Expression Regulation, drug effects; Mice; Osteogenesis, drug effects; Parathyroid Hormone, pharmacology; RANK Ligand, genetics, metabolism; Receptors, Glucocorticoid, metabolism; bone resorption; calcium-regulating hormones; osteoclasts; osteoporosis H. Herschel Conaway Petra Henning Antia Lie Jan Tuckermann Ulf H. Lerner article KalvisaSPCNSVTWMG2018 Insulin signaling and reduced glucocorticoid receptor activity attenuate postprandial gene expression in liver 2018 12 10 PLoS Biol. 16 e2006249 12 A. Kalvisa MS. Siersbæk SM. Præstholm LJL. Christensen R. Nielsen O. Stohr S. Vettorazzi J. Tuckermann M. White S. Mandrup L. Grøntved article MottaFBPSCBSZCT2018 Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the kelch domain substrate-recognition surface and enhance RAS-MAPK signaling 2018 11 27 Hum Mol Genet. 28 1007-1022 6 M. Motta M. Fidan E. Bellacchio F. Pantaleoni K. Schneider-Heieck S. Coppola G. Borck L. Salviati M. Zenker IC. Cirstea M. Tartaglia article KoenenCVCFBKBT2018 Glucocorticoid receptor in stromal cells is essential for glucocorticoid-mediated suppression of inflammation in arthritis 2018 11 Ann Rheum Dis. 77 1610-1618 11 M. Koenen S. Culemann S. Vettorazzi G. Caratti L. Frappart W. Baum G. Krönke U. Baschant J.P. Tuckermann article AramackiTEESBLAHGBLWKWGSSPZBRVWTSRWKRBHKS2018 Thirty-eight-negative kinase 1 mediates trauma-induced intestinal injury and multi-organ failure 2018 11 1 J Clin Invest. 128 5056-5072 11 M. Aramacki AK. Trugenberger AK. Ellwanger T. Eiseler C. Schwerdt L. Bettac D. Langgartner N. Azoitei R. Halbgebauer R. Groß T. Barth A. Lechel BM. Walter JM. Kraus C. Wiegreffe J. Grimm A. Scheffold MR. Schneider K. Peuker S. Zeißig S. Britsch S. Rose-John S. Vettorazzi E. Wolf A. Tannapfel K. Steinestel S. Reber P. Walther HA. Kestler P. Radermacher TF. Barth M. Huber-Lang A. Kleger T. Seufferlein article ScholtysekIBKSCPRWKSDTHFGSK2018 NR4A1 regulates motility of osteoclast precursors and serves as target for the modulation of systemic bone turnover 2018 11 J Bone Miner Res. 33 2035-2047 11 C. Scholtysek N. Ipseiz C. Böhm B. Krishnacoumar M. Stenzel T. Czerwinski K. Palumbo-Zerr T. Rothe D. Weidner A. Klej C. Stoll J. Distler J. Tuckermann M. Herrmann B. Fabry W. Goldmann G. Schett G. Krönke article AhmadKJRPT2018 Cell-based RNAi screening and high-content analysis in primary calvarian osteoblasts applied to identification of osteoblast differentiation regulators 2018 9 19 Sci Rep. 8 14045 1 M. Ahmad T. Kroll J. Jakob A. Rauch A. Ploubidou J. Tuckermann article PickeCBKSTWRVBSTSAHS2018 Thy-1 (CD90) promotes bone formation and protects against obesity 2018 8 8 Sci Transl Med. 10 453 AK. Picke GM. Campbell M. Blüher U. Krügel FN. Schmidt E. Tsourdi M. Winzer M. Rauner V. Vukicevic B. Busse J. Salbach-Hirsch JP. Tuckermann JC. Simon U. Anderegg LC. Hofbauer A. Saalbach article BallegeerLTEVTDSVWRTVTRIBBVL2018 Glucocorticoid receptor dimers control intestinal STAT1 and TNF-induced inflammation in mice 2018 8 1 J Clin Invest 128 3265-3279 8 M. Ballegeer K.V. Looveren S. Timmermans M. Eggermont S. Vandevyver F. Thery K. Dendoncker J. Souffriau J. Vandewalle L.V. Wyngene R. Rycke N. Takahashi P. Vandenabeele J. Tuckermann H.M. Reichardt F. Impens R. Beyaert K. Bosscher R.E. Vandenbroucke C. Libert article TanguduAVWLVLV2017 Scavenging reactive oxygen species production normalizes ferroportin expression and ameliorates cellular and systemic iron disbalances in hemolytic mouse model 2018 8 Antioxid Redox Signal 29 484-499 5 NK. Tangudu B. Alan F. Vinchi K. Wörle D. Lai S. Vettorazzi K. Leopold M. Vujić Spasić article UrbanczykSSJMM2018 Regulation of Energy Metabolism during Early B Lymphocyte Development 2018 7 27 Int J Mol Sci. 19 8 S. Urbanczyk M. Stein W. Schuh HM. Jäck D. Mougiakakos D. Mielenz article IgnatiusT2018 New horizons for osteoanabolic treatment? 2018 7 26 Nat Rev Endocrinol. 14 508-509 9 A. Ignatius J. Tuckermann article DharANKGCSYVLMSTSZK2018 Liver Cancer Initiation Requires p53 Inhibition by CD44-Enhanced Growth Factor Signaling 2018 6 11 Cancer Cell. 33 1061 - 1077 6 D. Dhar L. Antonucci H. Nakagawa J.Y. Kim E. Glitzner S. Caruso S. Shalapour L. Yang M.A. Valasek S. Lee K. Minnich E. Seki J. Tuckermann M. Sibilia J. Zucman-Rossi M. Karin article MullerZAdLKZKHVTvdGWC2018 Reduced expression of C/EBPβ-LIP extends health and lifespan in mice 2018 6 4 Elife C. Müller L.M. Zidek T. Ackermann T. de Jong P. Liu V. Kliche M.A. Zaini G. Kortman L. Harkema D.S. Verbeek J.P. Tuckermann J. von Maltzahn A. de Bruin V. Guryev Z.Q. Wang C.F. Calkhoven article LinderHGZHBRTSWS2018 EGFR controls bone development by negatively regulating mTOR-signaling during osteoblast differentiation 2018 6 Cell Death Differ. 25 1094-1106 6 M. Linder M. Hecking E. Glitzner K. Zwerina M. Holcmann L. Bakiri MG Ruocco J. Tuckermann G. Schett EF. Wagner M. Sibilia article RaunerBDGHHHJKKMSTZ2018 Osteoimmunology-IMMUNOBONE : Regulation of bone by inflammation 2018 5 Z Rheumatol 77 12-15 1 M. Rauner F. Buttgereit J. Distler A.I. Garbe M. Herrmann L. Hofbauer M. Hoffmann R. Jessberger U. Kornak G. Krönke S. Mundlos C. Spies J. Tuckermann J. Zwerina article KamradtADDGIKKPPSSTW2018 Mutual influence of immune system and bones 2018 5 Z Rheumatol 77 8-11 1 T. Kamradt M. Amling B. Dankbar A. Dudeck M. Gunzer A. Ignatius G. Krönke K. Kubatzky T. Pap I. Prinz G. Schett T. Schinke J. Tuckermann A. Waisman article RappHKKTI2017 Induced global deletion of glucocorticoid receptor impairs fracture healing 2018 4 FASEB J. 2017 32 2235-2245 4 A.E. Rapp Y. Hachemi J. Kemmler M. Koenen J. P. Tuckermann A. Ignatius article HachemiRPWIT2018 Molecular Mechanisms of Glucocorticoids on Skeleton and Regeneration after Fracture 2018 3 27 J Mol Endocrinol 61 R75 - R90 1 Y. Hachemi A. Rapp AK. Picke G. Weidinger A. Ignatius J. Tuckermann article BaakeJSRBTRFR2018 The glucocorticoid receptor in recipient cells keeps cytokine secretion in acute graft-versus-host disease at bay 2018 3 2 Oncotarget 9 15437-15450 21 T. Baake K. Jörß J. Suennemann L. Roßmann H. Bohnenberger J.P. Tuckermann HM. Reichhardt HJ. Fischer SD. Reichardt article BarteltBBKMSHOYDTAHSHN2018 Lrp1 in osteoblasts controls osteoclast activity and protects against osteoporosis by limiting PDGF-RANKL signaling 2018 2 26 Bone Res. 6 4 A. Bartelt F. Behler-Janbeck FT. Beil T. Koehne B. Müller T. Schmidt M. Heine L. Ochs T. Yilmaz M. Dietrich J.P. Tuckermann M. Amling J. Herz T. Schinke J. Heeren A. Niemeier article LaiTHWMTMDV2017 Hepatic Smad7-overexpression causes severe iron overload in the mouse. 2018 2 1 Blood 131 581-585 5 D. Lai F. Teng S. Hammad J. Werle T. Maas A. Teufel M. U. Muckenthaler S. Dooley M. Vujić Spasić article LeeLTJTTWHBFVBZT2017 Deletion of Menin in craniofacial osteogenic cells in mice elicits development of mandibular ossifying fibroma 2018 2 1 Oncogene 37 616-626 5 S. Lee P. Liu R. Teinturier J. Jakob M. Tschaffon A. Tasdogan R. Wittig S. Hoeller D. Baumhoer L. Frappart S. Vettorazzi P. Bertolino C. Zhang J. P. Tuckermann article HaffnerLuntzerKLMHLTI2018 Estrogen receptor α- (ERα), but not ERβ-signaling, is crucially involved in mechanostimulation of bone fracture healing by whole-body vibration 2018 1 20 Bone 11-20 110 M. Haffner-Luntzer A. Kovtun I. Lackner Y. Mödinger S. Hacker A. Liedert J. Tuckermann A. Ignatius article TuSFWCTCSZ2017 Endogenous glucocorticoid signaling in chondrocytes attenuates joint inflammation and damage. 2018 1 FASEB J. 32 478-487 1 J. Tu S. Stoner PD. Fromm T. Wang D. Chen J. P. Tuckermann M. S. Cooper MJ. Seibel H. Zhou article GaluppoVHSTBF2017 The glucocorticoid receptor in monocyte-derived macrophages is critical for cardiac infarct repair and remodeling 2017 11 FASEB J. 31 5122-5132 11 P. Galuppo S. Vettorazzi J. Hövelmann C.-J. Scholz J. P. Tuckermann J. Bauersachs D. Fracarollo article QuartaCZYJLYGLFBZFKKVLHBBLSGBPTHSCLSMDFT2017 Molecular Integration of Incretin and Glucocorticoid Action Reverses Immunometabolic Dysfunction and Obesity 2017 10 3 Cell Metab. 26 620-632 4 C. Quarta C. Clemmensen Z. Zhu B. Yang SS. Joseph D. Lutter CX. Yi C. García-Cáceres B. Legutko K. Fischer R. Brommage P. Zizzari BS. Franklin M. Krueger M. Koch S. Vettorazzi P. Li S. M. Hofmann M. Bakhti A. Bastidas-Ponce H. Lickert TM. Strom V. Gailus-Durner I. Bechmann D. Perez-Tilve J. P. Tuckermann M. Hrabě de Angelis D. Sandoval D. Cota E. Latz RJ. Seeley T. D. Müller RD. DiMarchi B. Finan M. H. Tschöp article HassnainWaqasNHAPSGR2017 Adipose tissue macrophages develop from bone marrow-independent progenitors in Xenopus laevis and mouse 2017 9 J Leukoc Biol. 102 845-855 3 CX3CR1; fat body; neuropeptide FF; yolk sac Mϕs SF. Hassnain Waqas A. Noble AC. Hoang G. Ampem M. Popp S. Strauß M. Guille T. Röszer article SteinDMBFRUSSBWJM2017 A defined metabolic state in pre B cells governs B-cell development and is counterbalanced by Swiprosin-2/EFhd1 2017 7 Cell Death Differ. 24 1239-1252 7 M. Stein S. Dütting D. Mougiakakos M. Bösl K. Fritsch D. Reimer S. Urbanczyk T. Steinmetz W. Schuh A. Bozec TH. Winkler H. M. Jäck D. Mielenz article PantaleoniLCMLBCLPFNCAST2017 Aberrant HRAS transcript processing underlies a distinctive phenotype within the RASopathy clinical spectrum 2017 7 Hum Mutat. 38 798-804 7 F. Pantaleoni D. Lev IC. Cirstea M. Motta FR. Lepri L. Bottero S. Cecchetti I. Linger S. Paolacci E. Flex A. Novelli A. Care MR. Ahmadian E. Stellacci M. Tartaglia article WaqasHLAABTCGNLMRPQASSBLSR2017 Neuropeptide FF increases M2 activation and self-renewal of adipose tissue macrophages 2017 6 30 J Clin Invest. 127 2842-2854 7 SFH. Waqas AC. Hoang JT. Lyn G. Ampem H. Azegrouz L. Balogh J. Thuroczy JC. Chen IC. Gerling S. Nam JS. Lim J. Martinez-Ibañez JT. Real S. Paschke R. Quillet S. Ayachi F. Simonin EM. Schneider JA. Brinkman DW. Lamming CM. Seroogy T. Röszer article WittigBlaichWSLBGSMLJCHSBM2017 Systematic screening of isogenic cancer cells identifies DUSP6 as context-specific synthetic lethal target in melanoma. 2017 4 4 Oncotarget 8 23760-23774 14 S. Wittig-Blaich R. Wittig S. Schmidt S. Lyer M. Bewerunge-Hudler S. Gronert-Sum O. Strobel-Freidekind C. Müller M. List A. Jaskot H. Christiansen M. Hafner D. Schadendorf I. Block J. Mollenhauer article LiuLKROLMLZNWRDBZT2017 Loss of menin in osteoblast lineage affects osteocyte-osteoclast crosstalk causing osteoporosis. 2017 4 Cell Death Differ. 24 672-682 4 P. Liu S. Lee J. Knoll A. Rauch S. Ostermay J. Luther N. Malkusch U. H. Lerner MM. Zaiss M. Neven R. Wittig M. Rauner J. P. David P. Bertolino CX. Zhang J. P. Tuckermann article MuellerHKVBMAJFEMTMHSBTM2016 Adipocyte Glucocorticoid Receptor Deficiency Attenuates Aging- and Hfd-Induced Obesity, and Impairs the Feeding-Fasting Transition. 2017 2 Diabetes 66 272-286 2 KM Mueller K. Hartmann D Kaltenecker S. Vettorazzi M. Bauer L. Mauser S Amann S. Jall K. Fischer H. Esterbauer T. D. Müller M. H. Tschöp C Magnes J. Haybaeck T Scherer N Bordag J. P. Tuckermann R. Moriggi article Roszer2016 Transcriptional control of apoptotic cell clearance by macrophage nuclear receptors. 2017 2 Apoptosis 22 284-294 2 T. Röszer article TanguduV2017 Heme Activates Macrophage Hepcidin Expression via Toll like Receptor 4 and Extracellular Signal-Regulated Kinases Signaling Pathway 2017 1 21 Clinical Pharmacology & Biopharmaceutics 6 166 Naveen Kumar Tangudu M. Vujić Spasić article KlasenKDVVLMTBLR2017 Airway Epithelial Cells Are Crucial Targets of Glucocorticoids in a Mouse Model of Allergic Asthma 2017 1 17 J Immunol. 199 48-61 1 C. Klaßen A. Karabinskaya L. Dejager S. Vettorazzi J. Van Moorleghem F. Luhder S.H. Meijsing J. P. Tuckermann H. Bohnenberger C. Libert H.M. Reichardt article LunovaSNLKSVHRJDVTS2017 Hepcidin knockout mice spontaneously develop chronic pancreatitis owing to cytoplasmic iron overload in acinar cells. 2017 1 J Pathol. 241 104-114 1 M. Lunova P. Schwarz R. Nuraldeen K. Levada D. Kuscuoglu M. Stützle M. Vujić Spasić J. Haybaeck P. Ruchala M. Jirsa JC. Deschemin S. Vaulont C. Trautwein P. Strnad article Pantaleoni2017 Aberrant HRAS transcript processing underlies a distinctive phenotype within the RASopathy clinical spectrum. RASopathies are a group of rare, clinically related conditions affecting development and growth, and are caused by germline mutations in genes encoding signal transducers and modulators with a role in the RAS signaling network. These disorders share facial dysmorphia, short stature, variable cognitive deficits, skeletal and cardiac defects, and a variable predisposition to malignancies. Here, we report on a de novo 10-nucleotide-long deletion in HRAS (c.481_490delGGGACCCTCT, NM_176795.4; p.Leu163ProfsTer52, NP_789765.1) affecting transcript processing as a novel event underlying a RASopathy characterized by developmental delay, intellectual disability and autistic features, distinctive coarse facies, reduced growth, and ectodermal anomalies. Molecular and biochemical studies demonstrated that the deletion promotes constitutive retention of exon IDX, which is generally skipped during HRAS transcript processing, and results in a stable and mildly hyperactive GDP/GTP-bound protein that is constitutively targeted to the plasma membrane. Our findings document a new mechanism leading to altered HRAS function that underlies a previously unappreciated phenotype within the RASopathy spectrum. 2017 jul 1098-1004 10.1002/humu.23224 Human mutation 38 798--804 Animals; Autistic Disorder, genetics; COS Cells; Cell Membrane, metabolism; Child; Child, Preschool; Chlorocebus aethiops; Developmental Disabilities, genetics; Exons; Facies; Gene Deletion; Gene Expression Regulation, Neoplastic; Genes, ras; Germ-Line Mutation; Humans; Intellectual Disability, genetics; Male; Phenotype; Proto-Oncogene Proteins p21(ras), genetics; RNA, Messenger, metabolism; Signal Transduction; Costello syndrome; HRAS; RAS signaling; RASopathies; transcript processing Francesca Pantaleoni Dorit Lev Ion C. Cirstea Marialetizia Motta Francesca Romana Lepri Lisabianca Bottero Serena Cecchetti Ilan Linger Stefano Paolacci Elisabetta Flex Antonio Novelli Alessandra Carè Mohammad R. Ahmadian Emilia Stellacci Marco Tartaglia article pmid27596806 Activation of dimeric glucocorticoid receptors in osteoclast progenitors potentiates RANKL induced mature osteoclast bone resorbing activity 2016 12 Bone 93 43-54 H. H. Conaway P. Henning A. Lie J. P. Tuckermann U. H. Lerner article BarcalaTabarrozziADCGABALVTDP2016 GR-independent down-modulation on GM-CSF bone marrow-derived dendritic cells by the selective glucocorticoid receptor modulator Compound A. 2016 11 18 Sci Rep. 6 36646 AE. Barcala Tabarrozzi L. Andreone J. Deckers CN. Castro ML. Gimeno L. Ariolfo PM. Berguer M. Antunica-Noguerol AC. Libermann S. Vettorazzi J. P. Tuckermann K. De Bosscher MJ Perone article JavaheriKPPKNSNSMHAWTLHTKMDURGKM2016 Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation 2016 10 13 Cell Death Dis. 7 e2419 10 T. Javaheri Z. Kazemi J Pencik HT Pham M. Kauer R Noorizadeh B Sax H Nivarthi M Schlederer B. Maurer M Hofbauer DN Aryee M Wiedner EM Tomazou M Logan C. Hartmann J. P. Tuckermann L. Kenner M Mikula H. Dolznig A Üren GH Richter F Grebien H. Kovar R. Moriggl article pmid27720451 Chemical <prt>H</prt>ybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease 2016 10 5 Cell 167 843-857 3 B. Finan C. Clemmensen Z. Zhu K. Stemmer K. Gauthier L. Müller M. De Angelis K. Moreth F. Neff D. Perez-Tilve K. Fischer D. Lutter M. A. Sanchez-Garrido P. Liu J. P. Tuckermann M. Malehmir M. E. Healy A. Weber M. Heikenwalder M. Jastroch M. Kleinert S. Jall S. Brandt F. Flamant K. W. Schramm H. Biebermann Y. Doring C. Weber K. M. Habegger M. Keuper V. Gelfanov F. Liu J. Köhrle J. Rozman H. Fuchs V. Gailus-Durner M. Hrabě de Angelis S. M. Hofmann B. Yang M. H. Tschöp R. DiMarchi T. D. Müller article pmid27554624 Dicer ablation in osteoblasts by Runx2 driven cre-loxP recombination affects bone integrity, but not glucocorticoid-induced suppression of bone formation 2016 8 24 Sci Rep 6 32112 P. Liu M. Baumgart M. Groth J. Wittmann H. M. Jäck M. Platzer J. P. Tuckermann U. Baschant article pmid27367288 High-Content Microscopy Analysis of Subcellular Structures:Assay Development and Application to Focal Adhesion Quantification 2016 7 1 Curr Protoc Cytom 77 1-12 T. Kroll D. Schmidt G. Schwanitz M. Ahmad J. Hamann C. Schlosser Y. C. Lin K. J. Böhm J. P. Tuckermann A. Ploubidou article pmid27129231 Transforming Growth Factor β1 (TGF-β1) Activates Hepcidin mRNA Expression in Hepatocytes 2016 6 17 J. Biol. Chem. 291 13160-13174 25 S. Chen T. Feng M. Vujić Spasić S. Altamura K. Breitkopf-Heinlein J. Altenoder T. S. Weiss S. Dooley M. U. Muckenthaler article pmid27191748 Combined experience of six independent laboratories attempting to create an Ewing sarcoma mouse model 2016 5 15 Oncotarget 23 34141-34163 8 T. Z. Minas D. Surdez T. Javaheri M. Tanaka M. Howarth H. J. Kang J. Han Z. Y. Han B. Sax B. E. Kream S. H. Hong H. Celik F. Tirode J. P. Tuckermann J. A. Toretsky L. Kenner H. Kovar S. Lee E. A. Sweet-Cordero T. Nakamura R. Moriggl O. Delattre A. Uren article pmid26639395 Decreased expression of the glucocorticoid receptor-GILZ pathway in Kupffer cells promotes liver inflammation in obese mice 2016 4 J. Hepatol. S0168-8278 781-783 15 O. Robert H. Boujedidi A. Bigorgne G. Ferrere C. S. Voican S. Vettorazzi J. P. Tuckermann L. Bouchet-Delbos T. Tran P. Hemon V. Puchois I. Dagher R. Douard F. Gaudin H. Gary-Gouy F. Capel I. Durand-Gasselin S. Prevot S. Rousset S. Naveau V. Godot D. Emilie M. Lombes G. Perlemuter A. M. Cassard article pmid26842265 Molecular Actions of Glucocorticoids in Cartilage and Bone During Health, Disease, and Steroid Therapy 2016 4 Physiol. Rev. 96 409-447 2 K. Hartmann M. Koenen S. Schauer S. Wittig-Blaich M. Ahmad U. Baschant J. P. Tuckermann article pmid26239911 Adipose tissue macrophages in non-rodent mammals: a comparative study 2016 2 Cell Tissue Res. 363 461-478 2 G. Ampem H. Azegrouz A. Bacsadi L. Balogh S. Schmidt J. Thuroczy T. Röszer article pmid26672929 Selepressin in Septic Shock: A Step Toward Decatecholaminization? 2016 1 Crit Care Med. 44 234-236 1 P. Asfar JA Russell J. P. Tuckermann P. Radermacher article pmid25910399 The glucocorticoid receptor in inflammatory processes: transrepression is not enough 2015 11 Biol. Chem. 396 1223-1231 11 S. Hübner L. Dejager C. Libert J. P. Tuckermann article pmid26183376 Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1 2015 7 17 Nat Commun 6 7796 S. Vettorazzi C. Bode L. Dejager L. Frappart E. Shelest C. Klassen A. Tasdogan H. M. Reichardt C. Libert M. Schneider F. Weih N. Henriette Uhlenhaut J. P. David M. Graler A. Kleiman J. P. Tuckermann article pmid25733567 ACTH controls thymocyte homeostasis independent of glucocorticoids 2015 6 FASEB J. 29 2526-2534 6 G. Talaber J. P. Tuckermann S. Okret article pmid25957148 Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo 2015 6 Genome Res. 25 836-844 6 H. W. Lim N. H. Uhlenhaut A. Rauch J. Weiner S. Hübner N. Hubner K. J. Won M. A. Lazar J. P. Tuckermann D. J. Steger article pmid26089604 Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms 2015 5 Mediators Inflamm. 2015 816460 T. Röszer article pmid25847991 Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy 2015 4 28 Proc. Natl. Acad. Sci. U.S.A. 112 5479-5484 17 L. C. Matthews A. A. Berry D. J. Morgan T. M. Poolman K. Bauer F. Kramer D. G. Spiller R. V. Richardson K. E. Chapman S. N. Farrow M. R. Norman A. J. Williamson A. D. Whetton S. S. Taylor J. P. Tuckermann M. R. White D. W. Ray article pmid25510234 Mast cell promotion of T cell-driven antigen-induced arthritis despite being dispensable for antibody-induced arthritis in which T cells are bypassed 2015 4 Arthritis Rheumatol 67 903-913 4 N. Schubert J. Dudeck P. Liu A. Karutz S. Speier M. Maurer J. P. Tuckermann A. Dudeck article pmid25358639 Glucocorticoids attenuate acute graft-versus-host disease by suppressing the cytotoxic capacity of CD8(+) T cells 2015 3 J. Pathol. 235 646-655 4 J. Theiss-Suennemann K. Jorss J. J. Messmann S. D. Reichardt E. Montes-Cobos F. Luhder J. P. Tuckermann H. Wolff R. Dressel H. J. Grone G. Strauss H. M. Reichardt article pmid25574839 Retinoid X receptors orchestrate osteoclast differentiation and postnatal bone remodeling 2015 2 J. Clin. Invest. 125 809-823 2 M. P. Menendez-Gutierrez T. Röszer L. Fuentes V. Nunez A. Escolano J. M. Redondo N. De Clerck D. Metzger A. F. Valledor M. Ricote article pmid26215995 Glucocorticoid-Induced Osteoporosis 2015 Adv. Exp. Med. Biol. 872 179-215 B. Frenkel W. White J. P. Tuckermann article pmid25333229 Stat5 gene dosage in T cells modulates CD8+ T-cell homeostasis and attenuates contact hypersensitivity response in mice 2015 1 Allergy 70 67-79 1 H. Nivarthi M. Prchal-Murphy A. Swoboda M. Hager M. Schlederer L. Kenner J. P. Tuckermann V. Sexl R. Moriggl O. Ermakova article NakhaeiRad2015 The Function of Embryonic Stem Cell-expressed RAS (E-RAS), a Unique RAS Family Member, Correlates with Its Additional Motifs and Its Structural Properties. E-RAS is a member of the RAS family specifically expressed in embryonic stem cells, gastric tumors, and hepatic stellate cells. Unlike classical RAS isoforms (H-, N-, and K-RAS4B), E-RAS has, in addition to striking and remarkable sequence deviations, an extended 38-amino acid-long unique N-terminal region with still unknown functions. We investigated the molecular mechanism of E-RAS regulation and function with respect to its sequence and structural features. We found that N-terminal extension of E-RAS is important for E-RAS signaling activity. E-RAS protein most remarkably revealed a different mode of effector interaction as compared with H-RAS, which correlates with deviations in the effector-binding site of E-RAS. Of all these residues, tryptophan 79 (arginine 41 in H-RAS), in the interswitch region, modulates the effector selectivity of RAS proteins from H-RAS to E-RAS features. 2015 jun 1083-351X 10.1074/jbc.M115.640607 The Journal of biological chemistry 290 15892--15903 Amino Acid Motifs; Animals; COS Cells; Chlorocebus aethiops; Dogs; Humans; Madin Darby Canine Kidney Cells; Oncogene Protein p21(ras), genetics, metabolism; Protein Structure, Tertiary; Proto-Oncogene Proteins p21(ras), genetics, metabolism; Sequence Homology, Amino Acid; Signal Transduction, physiology; E-RAS; H-RAS; RAS protein; Raf kinase; effector selection; embryonic stem cell-expressed RAS; phosphatidylinositide 3-kinase (PI 3-kinase); phosphatidylinositol kinase (PI kinase); small GTPase; specificity determining residues Saeideh Nakhaei-Rad Hossein Nakhaeizadeh Claus Kordes Ion C. Cirstea Malte Schmick Radovan Dvorsky Philippe I. H. Bastiaens Dieter Häussinger Mohammad Reza Ahmadian article pmid25940089 The Function of Embryonic Stem Cell-expressed RAS ERAS, a Unique RAS Family Member, Correlates with I Additional Motifs and Its Structural Properties 2015 J. Biol. Chem. 290 15892-15903 25 S. Nakhaei-Rad H. Nakhaeizadeh C. Kordes I. C. Cirstea M. Schmick R. Dvorsky P. I. Bastiaens D. Haussinger M. R. Ahmadian article pmid25193158 Disruption of glucocorticoid signaling in chondrocytes delays metaphyseal fracture healing but does not affect normal cartilage and bone development 2014 12 Bone 69 12-22 J. Tu H. Henneicke Y. Zhang S. Stoner T. L. Cheng A. Schindeler D. Chen J. P. Tuckermann M. S. Cooper M. J. Seibel H. Zhou article pmid25174684 The invertebrate midintestinal gland ('hepatopancreas') is an evolutionary forerunner in the integration of immunity and metabolism 2014 12 Cell Tissue Res. 358 685-695 3 T. Röszer article pmid25096715 FMRF-amide is a glucose-lowering hormone in the snail Helix aspersa 2014 11 Cell Tissue Res. 358 371-383 2 T. Röszer E. D. Kiss-Toth article pmid25306233 Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures 2014 11 Nat. Med. 20 1279-1288 11 P. Henning X. Liu K. Nagano H. Saito A. E. Borjesson K. Sjogren S. H. Windahl H. Farman B. Kindlund C. Engdahl A. Koskela F. P. Zhang E. E. Eriksson F. Zaman A. Hammarstedt H. Isaksson M. Bally A. Kassem C. Lindholm O. Sandberg P. Aspenberg L. Savendahl J. Q. Feng J. P. Tuckermann J. Tuukkanen M. Poutanen R. Baron U. H. Lerner F. Gori C. Ohlsson article pmid25057793 Glucocorticoids induce gastroparesis in mice through depletion of l-arginine 2014 10 Endocrinology 155 3899-3908 10 S. D. Reichardt T. Weinhage A. Rotte M. Foller M. Oppermann F. Luhder J. P. Tuckermann F. Lang J. van den Brandt H. M. Reichardt article pmid24965772 Bronchial epithelial cells induce alternatively activated dendritic cells dependent on glucocorticoid receptor signaling 2014 8 1 J. Immunol. 193 1475-1484 3 M. Weitnauer L. Schmidt N. Ng Kuet Leong S. Muenchau F. Lasitschka V. Eckstein S. Hübner J. P. Tuckermann A. H. Dalpke article pmid24862220 Glucocorticoid receptor in prostate epithelia is not required for corticosteroid-induced epithelial hyperproliferation in the mouse prostate 2014 7 Prostate 74 1068-1078 10 B. Zhao J. P. Choi M. Jaehne Y. R. Gao R. Desai J. P. Tuckermann H. Zhou D. J. Handelsman U. Simanainen article pmid24836782 Steroids and vasopressin in septic shock-brother and sister or just distant cousins? 2014 6 Crit. Care Med. 42 1531-1532 6 P. Asfar J. P. Tuckermann P. Radermacher book Roszer2014_2 Nitric Oxide in Plants: Metabolism and Role in Stress Physiology 2014 5 27 978-3-319-06709-4 Springer International Publishing M. Nasir Khan Mohammad Mobin Firoz Mohammad Francisco J. Corpas T. Röszer book Roszer2014 Nitric Oxide Signaling and Nitrosative Stress in the Musculoskeletal System 2014 5 3 978-3-642-30017-2 Springer Berlin Heidelberg Ismail Laher T. Röszer article pmid24488308 Chemokine-mediated redirection of <prt>T cells constitutes a critical mechanism of glucocorticoid therapy in autoimmune CNS responses</prt> 2014 5 Acta Neuropathol. 127 713-729 5 N. Schweingruber H. J. Fischer L. Fischer J. van den Brandt A. Karabinskaya V. Labi A. Villunger B. Kretzschmar P. Huppke M. Simons J. P. Tuckermann A. Flugel F. Luhder H. M. Reichardt article pmid24343796 Leptin receptor deficient diabetic (db/db) mice are compromised in postnatal bone regeneration 2014 4 Cell Tissue Res. 356 195-206 1 T. Röszer T. Jozsa E. D. Kiss-Toth N. De Clerck L. Balogh article pmid24653703 Molecular basis of HFE-hemochromatosis 2014 3 11 Front Pharmacol 5 42 M. Vujić Spasić article pmid24705357 Activating mutations in RRAS underlie a phenotype within the RA Sopathy spectrum and contribute to leukaemogenesis 2014 Hum. Mol. Genet. 23 4315-4327 16 E. Flex M. Jaiswal F. Pantaleoni S. Martinelli M. Strullu E. K. Fansa A. Caye A. De Luca F. Lepri R. Dvorsky L. Pannone S. Paolacci S. C. Zhang V. Fodale G. Bocchinfuso C. Rossi E. M. Burkitt-Wright A. Farrotti E. Stellacci S. Cecchetti R. Ferese L. Bottero S. Castro O. Fenneteau B. Brethon M. Sanchez A. E. Roberts H. G. Yntema I. Van Der Burgt P. Cianci M. L. Bondeson M. Cristina Digilio G. Zampino B. Kerr Y. Aoki M. L. Loh A. Palleschi E. Di Schiavi A. Care A. Selicorni B. Dallapiccola I. C. Cirstea L. Stella M. Zenker B. D. Gelb H. Cave M. R. Ahmadian M. Tartaglia article pmid24443565 Functional cross-talk between ras and rho pathways: a Ras-specific GTP ase-activating protein p120 Ras GAP competitively inhibits the Rho GAP activity of deleted in liver cancer DLC tumor suppressor by masking the catalytic arginine finger 2014 J. Biol. Chem. 289 6839-6849 10 M. Jaiswal R. Dvorsky E. Amin S. L. Risse E. K. Fansa S. C. Zhang M. S. Taha A. R. Gauhar S. Nakhaei-Rad C. Kordes K. T. Koessmeier I. C. Cirstea M. A. Olayioye D. Haussinger M. R. Ahmadian article pmid25014207 Liposome reconstitution and modulation of recombinant prenylated human Rac1 by GEFG DI1 and Pak1 2014 PLoS ONE 9 e102425 7 S. C. Zhang L. Gremer H. Heise P. Janning A. Shymanets I. C. Cirstea E. Krause B. Nurnberg M. R. Ahmadian article pmid23769823 Molecular determinants of glucocorticoid actions in inflammatory joint diseases 2013 11 5 Mol. Cell. Endocrinol. 380 108-118 1-2 U. Baschant S. Culemann J. P. Tuckermann article pmid23885015 Effects of the selective glucocorticoid receptor modulator compound A on bone metabolism and inflammation in male mice with collagen-induced arthritis 2013 10 Endocrinology 154 3719-3728 10 M. Rauner S. Thiele K. Sinningen M. Winzer J. Salbach-Hirsch I. Gloe K. Peschke G. Haegeman J. P. Tuckermann L. C. Hofbauer article pmid23701753 Retinoid X receptors in macrophage biology 2013 9 Trends Endocrinol. Metab. 24 460-468 9 T. Röszer M. P. Menendez-Gutierrez M. Cedenilla M. Ricote article pmid23754379 Inflammatory monocytes and Fc'ce'b3 receptor IV on osteoclasts are critical for bone destruction during inflammatory arthritis in mice 2013 6 25 Proc. Natl. Acad. Sci. U.S.A. 110 10729-10734 26 M. Seeling U. Hillenhoff J. P. David G. Schett J. P. Tuckermann A. Lux F. Nimmerjahn article pmid23696835 Deletion of mesenchymal glucocorticoid receptor attenuates embryonic lung development and abdominal wall closure 2013 5 16 PLoS ONE 8 e63578 5 A. Li R. Hardy S. Stoner J. P. Tuckermann M. Seibel H. Zhou article pmid23542786 PPAR'ce'b2/'ce'b4 governs Wnt signaling and bone turnover 2013 5 Nat. Med. 19 608-613 5 C. Scholtysek J. Katzenbeisser H. Fu S. Uderhardt N. Ipseiz C. Stoll M. M. Zaiss M. Stock L. Donhauser C. Böhm A. Kleyer A. Hess K. Engelke J. P. David F. Djouad J. P. Tuckermann B. Desvergne G. Schett G. Krönke article pmid23395800 The transcription factor early B-cell factor 1 regulates bone formation in an osteoblast-nonautonomous manner 2013 3 18 FEBS Lett. 587 711-716 6 T. Zee S. Boller I. Gyory M. P. Makinistoglu J. P. Tuckermann R. Grosschedl G. Karsenty article pmid23384835 New insights into the anti-inflammatory mechanisms of glucocorticoids: an emerging role for glucocorticoid-receptor-mediated transactivation 2013 3 Endocrinology 154 993-1007 3 S. Vandevyver L. Dejager J. P. Tuckermann C. Libert article pmid22983584 The murine growth differentiation factor 15 is not essential for systemic iron homeostasis in phlebotomized mice 2013 3 Haematologica 98 444-447 3 G. Casanovas M. Vujić Spasić C. Casu S. Rivella J. Strelau K. Unsicker M. U. Muckenthaler article pmid23059812 Diverging gain-of-function mechanisms of two novel KRAS mutations associated with Noonan and cardio-facio-cutaneous syndromes 2013 Hum. Mol. Genet. 22 262-270 2 I. C. Cirstea L. Gremer R. Dvorsky S. C. Zhang R. P. Piekorz M. Zenker M. R. Ahmadian article pmid22960056 Smad6 and Smad7 are co-regulated with hepcidin in mouse models of iron overload 2013 1 Biochim. Biophys. Acta 1832 76-84 1 M. Vujić Spasić R. Sparla K. Mleczko-Sanecka M. C. Migas K. Breitkopf-Heinlein S. Dooley S. Vaulont R. E. Fleming M. U. Muckenthaler article pmid22806960 Liver X receptors orchestrate osteoblast/osteoclast crosstalk and counteract pathologic bone loss 2012 12 J. Bone Miner. Res. 27 2442-2451 12 A. Kleyer C. Scholtysek E. Bottesch U. Hillienhof C. Beyer J. H. Distler J. P. Tuckermann G. Schett G. Krönke article pmid23045254 The multiple facets of glucocorticoid action in rheumatoid arthritis 2012 11 Nat Rev Rheumatol 8 645-655 11 U. Baschant N. E. Lane J. P. Tuckermann article pmid22714558 Selective glucocorticoid receptor modulation maintains bone mineral density in mice 2012 11 J. Bone Miner. Res. 27 2242-2250 11 S. Thiele N. Ziegler E. Tsourdi K. De Bosscher J. P. Tuckermann L. C. Hofbauer M. Rauner article pmid22564914 Hepatic growth hormone and glucocorticoid receptor signaling in body growth, steatosis and metabolic liver cancer development 2012 9 25 Mol. Cell. Endocrinol. 361 1-11 1-2 K. M. Mueller M. Themanns K. Friedbichler J. W. Kornfeld H. Esterbauer J. P. Tuckermann R. Moriggl article pmid22371175 Estradiol increases hematopoietic stem and progenitor cells independent of its actions on bone 2012 8 Haematologica 97 1131-1135 8 A. Illing P. Liu S. Ostermay A. Schilling G. de Haan A. Krust M. Amling P. Chambon T. Schinke J. P. Tuckermann article pmid22465035 Quantitative magnetic analysis reveals ferritin-like iron as the most predominant iron-containing species in the murine Hfe-haemochromatosis 2012 7 Biochim. Biophys. Acta 1822 1147-1153 7 L. Gutierrez M. Vujić Spasić M. U. Muckenthaler F. J. Lazaro article pmid22745741 Hfe deficiency impairs pulmonary neutrophil recruitment in response to inflammation 2012 6 21 PLoS ONE 7 e39363 6 K. Benesova M. Vujić Spasić S. M. Schaefer J. Stolte T. Baehr-Ivacevic K. Waldow Z. Zhou U. Klingmueller V. Benes M. A. Mall M. U. Muckenthaler article pmid22585571 Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation 2012 6 J. Clin. Invest. 122 2130-2140 6 S. Vandevyver L. Dejager T. Van Bogaert A. Kleyman Y. Liu J. P. Tuckermann C. Libert article pmid25436536 Molecular mechanisms of the glucocorticoid receptor in steroid therapy - lessons from transgenic mice 2012 6 Biomol Concepts 3 241-253 3 S. Hübner J. P. Tuckermann article pmid22354783 A cell-autonomous role for the glucocorticoid receptor in skeletal muscle atrophy induced by systemic glucocorticoid exposure 2012 5 1 Am. J. Physiol. Endocrinol. Metab. 302 10 E1210-1220 10 M. L. Watson L. M. Baehr H. M. Reichardt J. P. Tuckermann S. C. Bodine J. D. Furlow article pmid22344264 RSK2 protects mice against TNF-induced bone loss 2012 5 1 J. Cell. Sci. 125 2160-2171 Pt 9 C. Böhm A. Derer R. Axmann U. Hillienhof M. M. Zaiss J. Luther C. Zech M. Stock C. Scholtysek K. Engelke A. Hess J. P. Tuckermann G. Schett J. P. David article pmid22294744 Glucocorticoids enhance intestinal glucose uptake via the dimerized glucocorticoid receptor in enterocytes 2012 4 Endocrinology 153 1783-1794 4 S. D. Reichardt M. Foller R. Rexhepaj G. Pathare K. Minnich J. P. Tuckermann F. Lang H. M. Reichardt article pmid21524675 FMRFamide-related peptides: anti-opiate transmitters acting in apoptosis 2012 3 Peptides 34 177-185 1 T. Röszer G. Banfalvi article pmid22042221 Glucocorticoid receptor dimerization is required for survival in septic shock via suppression of interleukin-1 in macrophages 2012 2 FASEB J. 26 722-729 2 A. Kleiman S. Hübner J. M. Rodriguez Parkitna A. Neumann S. Hofer M. A. Weigand M. Bauer W. Schmid G. Schutz C. Libert H. M. Reichardt J. P. Tuckermann article pmid21797849 Two novel germline KRAS mutations: expanding the molecular and clinical phenotype 2012 Clin. Genet. 81 590-594 6 Z. Stark G. Gillessen-Kaesbach M. M. Ryan I. C. Cirstea L. Gremer M. R. Ahmadian R. Savarirayan M. Zenker book Roszer2012 The Biology of Subcellular Nitric Oxide 2012 978-94-007-2819-6 Springer Netherlands T. Röszer article pmid22242855 Biology and therapeutic applications of peroxisome proliferator- activated receptors 2012 Curr Top Med Chem 12 548-584 6 M. P. Menendez-Gutierrez T. Röszer M. Ricote article pmid23209701 Pharmacological estrogen administration causes a FSH-independent osteo-anabolic effect requiring ER alpha in osteoblasts 2012 PLoS ONE 7 e50301 11 S. Seitz J. Keller A. F. Schilling A. Jeschke R. P. Marshall B. D. Stride T. Wintermantel F. T. Beil M. Amling G. Schutz J. P. Tuckermann T. Schinke article pmid21646349 Tumor necrosis factor inhibits glucocorticoid receptor function in mice: a strong signal toward lethal shock 2011 J. Biol. Chem. 286 26555-26567 30 T. Van Bogaert S. Vandevyver L. Dejager F. Van Hauwermeiren I. Pinheiro I. Petta D. Engblom A. Kleyman G. Schutz J. P. Tuckermann C. Libert article pmid21364282 The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice 2011 J. Clin. Invest. 121 1386-1396 4 M. Castoldi M. Vujić Spasić S. Altamura J. Elmen M. Lindow J. Kiss J. Stolte R. Sparla L. A. D'Alessandro U. Klingmueller R. E. Fleming T. Longerich H. J. Grone V. Benes S. Kauppinen M. W. Hentze M. U. Muckenthaler article pmid20824698 Synergistic activation by p38 MAPK and glucocorticoid signaling mediates induction of M2-like tumor-associated macrophages expressing the novel CD20 homolog MS4 A8 A 2011 Int. J. Cancer 129 122-132 1 A. Schmieder K. Schledzewski J. Michel J. P. Tuckermann L. Tome C. Sticht C. Gkaniatsou J. P. Nicolay A. Demory J. Faulhaber J. Kzhyshkowska C. Geraud S. Goerdt article pmid21715325 Retinoids stimulate periosteal bone resorption by enhancing the protein RANKL, a response inhibited by monomeric glucocorticoid receptor 2011 J. Biol. Chem. 286 31425-31436 36 H. H. Conaway A. Pirhayati E. Persson U. Pettersson O. Svensson C. Lindholm P. Henning J. P. Tuckermann U. H. Lerner article pmid22008357 Pyloric atresia associated with Dieulafoy lesion and gastric dysmotility in a neonate 2011 J. Pediatr. Surg. 46 19-23 10 E. Polonkai A. Nagy I. Csizy C. Molnar T. Röszer G. Balla T. Jozsa article pmid21723510 Molecular control of systemic bile acid homeostasis by the liver glucocorticoid receptor 2011 Cell Metab. 14 123-130 1 A. J. Rose M. Berriel Diaz A. Reimann J. Klement T. Walcher A. Krones-Herzig O. Strobel J. Werner A. Peters A. Kleyman J. P. Tuckermann A. Vegiopoulos S. Herzig article pmid21454492 Mechanistic insights into specificity, activity, and regulatory elements of the regulator of G-protein signaling RGS-containing Rho-specific guanine nucleotide exchange factors GEFs p115, PDZR GEF PRG, and leukemia-associated Rho GEFLARG 2011 J. Biol. Chem. 286 18202-18212 20 M. Jaiswal L. Gremer R. Dvorsky L. C. Haeusler I. C. Cirstea K. Uhlenbrock M. R. Ahmadian article pmid21199332 Histamine and H1 -histamine receptors faster venous circulation 2011 J. Cell. Mol. Med. 15 2614-2623 12 Z. Galajda J. Balla A. J. Szentmiklosi T. Biro G. Czifra N. Dobrosi A. Cseppento L. Patonay T. Röszer G. Balla L. M. Popescu I. Lekli A. Tosaki article pmid20845059 Inflammation as death or life signal in diabetic fracture healing 2011 Inflamm. Res. 60 3-10 1 T. Röszer article pmid21918186 Liposomal encapsulation of glucocorticoids alters their mode of action in the treatment of experimental autoimmune encephalomyelitis 2011 J. Immunol. 187 4310-4318 8 N. Schweingruber A. Haine K. Tiede A. Karabinskaya J. van den Brandt S. Wust J. M. Metselaar R. Gold J. P. Tuckermann H. M. Reichardt F. Luhder article pmid22084093 Glucocorticoid therapy of antigen-induced arthritis depends on the dimerized glucocorticoid receptor in T cells 2011 Proc. Natl. Acad. Sci. U.S.A. 108 19317-19322 48 U. Baschant L. Frappart U. Rauchhaus L. Bruns H. M. Reichardt T. Kamradt R. Brauer J. P. Tuckermann article pmid21804188 Disruption of the histone acetyltransferase MYST 4 leads to a Noonan syndrome-like phenotype and hyperactivated MAPK signaling in humans and mice 2011 J. Clin. Invest. 121 3479-3491 9 M. Kraft I. C. Cirstea A. K. Voss T. Thomas I. Goehring B. N. Sheikh L. Gordon H. Scott G. K. Smyth M. R. Ahmadian U. Trautmann M. Zenker M. Tartaglia A. Ekici A. Reis H. G. Dorr A. Rauch C. T. Thiel article pmid21233489 An anti-inflammatory selective glucocorticoid receptor modulator preserves osteoblast differentiation 2011 FASEB J. 25 1323-1332 4 A. Rauch V. Gossye D. Bracke E. Gevaert P. Jacques K. Van Beneden B. Vandooren M. Rauner L. C. Hofbauer G. Haegeman D. Elewaut J. P. Tuckermann K. De Bosscher article pmid20949621 Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders 2011 Hum. Mutat. 32 33-43 1 L. Gremer T. Merbitz-Zahradnik R. Dvorsky I. C. Cirstea C. P. Kratz M. Zenker A. Wittinghofer M. R. Ahmadian article pmid21135166 Autoimmune kidney disease and impaired engulfment of apoptotic cells in mice with macrophage peroxisome proliferator-activated receptor gamma or retinoid X receptor alpha deficiency 2011 J. Immunol. 186 621-631 1 T. Röszer M. P. Menendez-Gutierrez M. I. Lefterova D. Alameda V. Nunez M. A. Lazar T. Fischer M. Ricote article pmid21167214 Artificial linear episome-based protein expression system for protozoon Leishmania tarentolae 2011 Mol. Biochem. Parasitol. 176 69-79 2 S. Kushnir I. C. Cirstea L. Basiliya N. Lupilova R. Breitling K. Alexandrov article pmid21084452 Dissociation of osteogenic and immunological effects by the selective glucocorticoid receptor agonist, compound A, in human bone marrow stromal cells 2011 Endocrinology 152 103-112 1 M. Rauner C. Goettsch N. Stein S. Thiele M. Bornhaeuser K. De Bosscher G. Haegeman J. P. Tuckermann L. C. Hofbauer article pmid20956975 DNA binding-dependent glucocorticoid receptor activity promotes adipogenesis via Kr'fcppel-like factor 15 gene expression 2011 Lab. Invest. 91 203-215 2 M. Asada A. Rauch H. Shimizu H. Maruyama S. Miyaki M. Shibamori H. Kawasome H. Ishiyama J. P. Tuckermann H. Asahara article pmid21849763 Double unfurled dartos flap technique in the surgical treatment of recurrent urethrocutaneous fistulas 2011 Urol. Int. 87 380-384 4 T. Jozsa I. Csizy A. Csiszko M. Boros T. Röszer P. Nyirady article pmid21486951 Elevated Fra-1 expression causes severe lipodystrophy 2011 J. Cell. Sci. 124 1465-1476 Pt 9 J. Luther F. Driessler M. Megges A. Hess B. Herbort V. Mandic M. M. Zaiss A. Reichardt C. Zech J. P. Tuckermann C. F. Calkhoven E. F. Wagner G. Schett J. P. David article pmid20798244 Thymus-derived glucocorticoids mediate androgen effects on thymocyte homeostasis 2010 FASEB J. 24 5043-5051 12 Y. Chen S. Qiao J. P. Tuckermann S. Okret M. Jondal article pmid20346397 The role of the glucocorticoid receptor in inflammation and immunity 2010 J. Steroid Biochem. Mol. Biol. 120 69-75 2-3 U. Baschant J. P. Tuckermann article pmid21088502 The centrosome and mitotic spindle apparatus in cancer and senescence 2010 Cell Cycle 9 4469-4473 22 S. Schmidt F. Essmann I. C. Cirstea F. Kuck H. C. Thakur M. Singh A. Kletke R. U. Janicke C. Wiek H. Hanenberg M. R. Ahmadian K. Schulze-Osthoff B. Nurnberg R. P. Piekorz article pmid20729911 The centrosomal protein TAC C3 controls paclitaxel sensitivity by modulating a premature senescence program 2010 Oncogene 29 6184-6192 46 S. Schmidt L. Schneider F. Essmann I. C. Cirstea F. Kuck A. Kletke R. U. Janicke C. Wiek H. Hanenberg M. R. Ahmadian K. Schulze-Osthoff B. Nurnberg R. P. Piekorz article pmid20704761 Systems analysis of iron metabolism: the network of iron pools and fluxes 2010 BMC Syst Biol 4 112 T. J. Lopes T. Luganskaja M. Vujić Spasić M. W. Hentze M. U. Muckenthaler K. Schumann J. G. Reich article pmid20693657 Purification and crystallization of human Cu Zn superoxide dismutase recombinantly produced in the protozoan Leishmania tarentolae 2010 Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 66 871-877 Pt 8 E. M. Gazdag I. C. Cirstea R. Breitling J. Lukes W. Blankenfeldt K. Alexandrov article pmid20525385 Prednisolone-induced differential gene expression in mouse liver carrying wild type or a dimerization-defective glucocorticoid receptor 2010 BMC Genomics 11 359 R. Frijters W. Fleuren E. J. Toonen J. P. Tuckermann H. M. Reichardt H. van der Maaden A. van Elsas M. J. van Lierop W. Dokter J. de Vlieg W. Alkema article pmid20519330 Meeting report: nuclear receptors: transcription factors and drug targets connecting basic research with translational medicine 2010 Mol. Endocrinol. 24 1311-1321 7 J. P. Tuckermann W. Bourguet S. Mandrup article pmid20613959 PPARs in the Renal Regulation of Systemic Blood Pressure 2010 PPAR Res 2010 698730 T. Röszer M. Ricote article pmid20508742 Inflammatory mediators and insulin resistance in obesity: role of nuclear receptor signaling in macrophages 2010 Mediators Inflamm. 2010 219583 L. Fuentes T. Röszer M. Ricote article pmid20010698 Increased skeletal VEGF enhances beta-catenin activity and results in excessively ossified bones 2010 EMBO J. 29 424-441 2 C. Maes S. Goossens S. Bartunkova B. Drogat L. Coenegrachts I. Stockmans K. Moermans O. Nyabi K. Haigh M. Naessens L. Haenebalcke J. P. Tuckermann M. Tjwa P. Carmeliet V. Mandic J. P. David A. Behrens A. Nagy G. Carmeliet J. J. Haigh article pmid20953631 Hypothermia translocates nitric oxide synthase from cytosol to membrane in snail neurons 2010 Cell Tissue Res. 342 191-203 2 T. Röszer E. Kiss-Toth D. Rozsa T. Jozsa A. J. Szentmiklosi G. Banfalvi article pmid20519123 Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor 2010 Cell Metab. 11 517-531 6 A. Rauch S. Seitz U. Baschant A. F. Schilling A. Illing B. Stride M. Kirilov V. Mandic A. Takacz R. Schmidt-Ullrich S. Ostermay T. Schinke R. Spanbroek M. M. Zaiss P. E. Angel U. H. Lerner J. P. David H. M. Reichardt M. Amling G. Schutz J. P. Tuckermann article pmid20690180 Commensal microflora and interferon-gamma promote steady-state interleukin-7 production in vivo 2010 Eur. J. Immunol. 40 2391-2400 9 S. Shalapour K. Deiser O. Sercan J. P. Tuckermann K. Minnich G. Willimsky T. Blankenstein G. J. Hammerling B. Arnold T. Schuler article pmid19966803 A restricted spectrum of NRAS mutations causes Noonan syndrome 2010 Nat. Genet. 42 27-29 1 I. C. Cirstea K. Kutsche R. Dvorsky L. Gremer C. Carta D. Horn A. E. Roberts F. Lepri T. Merbitz-Zahradnik R. König C. P. Kratz F. Pantaleoni M. L. Dentici V. A. Joshi R. S. Kucherlapati L. Mazzanti S. Mundlos M. A. Patton M. C. Silengo C. Rossi G. Zampino C. Digilio L. Stuppia E. Seemanova L. A. Pennacchio B. D. Gelb B. Dallapiccola A. Wittinghofer M. R. Ahmadian M. Tartaglia M. Zenker article pmid19796705 Lipotoxicity in macrophages: evidence from diseases associated with the metabolic syndrome 2010 Biochim. Biophys. Acta 1801 327-337 3 X. Prieur T. Röszer M. Ricote article pmid19842906 Short-term adaptation of rat intestine to ileostomy: implication for pediatric practice 2009 J Invest Surg 22 292-300 4 T. Jozsa A. Magyar T. Cserni A. J. Szentmiklosi K. Erdelyi Z. Kincses G. Rakoczy G. Balla T. Röszer article pmid19997594 Therapeutic and adverse effects of a non-steroidal glucocorticoid receptor ligand in a mouse model of multiple sclerosis 2009 PLoS ONE 4 e8202 12 S. Wust D. Tischner M. John J. P. Tuckermann C. Menzfeld U. K. Hanisch J. van den Brandt F. Luhder H. M. Reichardt article pmid19385703 A cost-effective amino-acid-type selective isotope labeling of proteins expressed in Leishmania tarentolae 2009 J. Biomol. Struct. Dyn. 26 755-761 6 S. Foldynova-Trantirkova J. Matulova V. Dotsch F. Lohr I. C. Cirstea K. Alexandrov R. Breitling J. Lukes L. Trantirek article pmid19821526 In vivo phosphoenolpyruvate carboxykinase promoter mapping identifies disrupted hormonal synergism as a target of inflammation during sepsis in mice 2009 Hepatology 50 1963-1971 6 E. Chichelnitskiy A. Vegiopoulos M. Berriel Diaz A. Ziegler A. Kleiman A. Rauch J. P. Tuckermann S. Herzig article pmid19036879 Conditional inactivation of glucocorticoid receptor gene in dopamine-beta-hydroxylase cells impairs chromaffin cell survival 2009 Endocrinology 150 1775-1781 4 R. Parlato C. Otto J. P. Tuckermann S. Stotz S. Kaden H. J. Grone K. Unsicker G. Schutz article pmid19255787 Acetylcholine inhibits nitric oxide (NO) synthesis in the gastropod nervous system 2009 Cell Tissue Res. 336 325-335 2 T. Röszer T. Jozsa A. J. Szentmiklosi G. Banfalvi article pmid19283081 PPARgamma in Kidney Physiology and Pathophysiology 2008 PPAR Res 2008 183108 E. Kiss-Toth T. Röszer article pmid18523311 Peripheral T cells are the therapeutic targets of glucocorticoids in experimental autoimmune encephalomyelitis 2008 J. Immunol. 180 8434-8443 12 S. Wust J. van den Brandt D. Tischner A. Kleiman J. P. Tuckermann R. Gold F. Luhder H. M. Reichardt article pmid18981157 Oncostatin M-induced and constitutive activation of the JAK2/STAT5/CIS pathway suppresses CCL1, but not CCL7 and CCL8, chemokine expression 2008 J. Immunol. 181 7341-7349 10 C. Hintzen C. Haan J. P. Tuckermann P. C. Heinrich H. M. Hermanns article pmid18022390 Nuclear receptors in macrophages: a link between metabolism and inflammation 2008 FEBS Lett. 582 106-116 1 A. Szanto T. Röszer article pmid18249176 Hfe acts in hepatocytes to prevent hemochromatosis 2008 Cell Metab. 7 173-178 2 M. Vujić Spasić J. Kiss T. Herrmann B. Galy S. Martinache J. Stolte H. J. Grone W. Stremmel M. W. Hentze M. U. Muckenthaler article pmid18787189 Critical role of macrophages in glucocorticoid driven vascular calcification in a mouse-model of atherosclerosis 2008 Arterioscler. Thromb. Vasc. Biol. 28 2158-2164 12 M. R. Preusch M. Rattazzi C. Albrecht U. Merle J. P. Tuckermann G. Schutz E. Blessing G. Zoppellaro P. Pauletto R. Krempien M. E. Rosenfeld H. A. Katus F. Bea article pmid18703503 Cell-specific regulation of PTX3 by glucocorticoid hormones in hematopoietic and nonhematopoietic cells 2008 J. Biol. Chem. 283 29983-29992 44 A. Doni G. Mantovani C. Porta J. P. Tuckermann H. M. Reichardt A. Kleiman M. Sironi L. Rubino F. Pasqualini M. Nebuloni S. Signorini G. Peri A. Sica P. Beck-Peccoz B. Bottazzi A. Mantovani article pmid18039792 Glucocorticoid receptor is required for skin barrier competence 2008 Endocrinology 149 1377-1388 3 P. Bayo A. Sanchis A. Bravo J. L. Cascallana K. Buder J. P. Tuckermann G. Schutz P. Perez article pmid17446934 Macrophages and neutrophils are the targets for immune suppression by glucocorticoids in contact allergy 2007 J. Clin. Invest. 117 1381-1390 5 J. P. Tuckermann A. Kleiman R. Moriggl R. Spanbroek A. Neumann A. Illing B. E. Clausen B. Stride I. Forster A. J. Habenicht H. M. Reichardt F. Tronche W. Schmid G. Schutz article pmid16946298 STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation 2007 Blood 109 353-358 1 M. V. Verga Falzacappa M. Vujić Spasić R. Kessler J. Stolte M. W. Hentze M. U. Muckenthaler article pmid17264297 Physiologic systemic iron metabolism in mice deficient for duodenal Hfe 2007 Blood 109 4511-4517 10 M. Vujić Spasić J. Kiss T. Herrmann R. Kessler J. Stolte B. Galy B. Rathkolb E. Wolf W. Stremmel M. W. Hentze M. U. Muckenthaler article pmid18025775 Modulation of adenosine-induced responses in the guinea-pig trachea during long-term caffeine treatment: possible role of epithelium 2007 J. Pharmacol. Sci. 105 279-290 3 L. Brugos R. Gesztelyi J. Zsuga A. Cseppento I. Benko Z. Galajda G. Deak S. Sipka T. Röszer P. Kovacs M. Szilasi I. Edes A. J. Szentmiklosi article pmid17982078 JunB is required for IgE-mediated degranulation and cytokine release of mast cells 2007 J. Immunol. 179 6873-6880 10 B. Textor A. H. Licht J. P. Tuckermann R. Jessberger E. Razin P. Angel M. Schorpp-Kistner B. Hartenstein article pmid17587493 Glucocorticoid receptor action in beneficial and side effects of steroid therapy: lessons from conditional knockout mice 2007 Mol. Cell. Endocrinol. 275 98-108 1-2 A. Kleiman J. P. Tuckermann article pmid17603917 Expression profiling of Dexamethasone-treated primary chondrocytes identifies targets of glucocorticoid signalling in endochondral bone development 2007 BMC Genomics 8 205 C. G. James V. Ulici J. P. Tuckermann T. M. Underhill F. Beier article pmid17636038 Dual specificity phosphatase 1 knockout mice show enhanced susceptibility to anaphylaxis but are sensitive to glucocorticoids 2007 Mol. Endocrinol. 21 2663-2671 11 J. V. Maier S. Brema J. P. Tuckermann U. Herzer M. Klein M. Stassen A. Moorthy A. C. Cato article pmid16880258 Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1 2006 J. Exp. Med. 203 1883-1889 8 S. M. Abraham T. Lawrence A. Kleiman P. Warden M. Medghalchi J. P. Tuckermann J. Saklatvala A. R. Clark article pmid16716119 Common pathway of chromosome condensation in Mammalian cells 2006 DNA Cell Biol. 25 295-301 5 G. Banfalvi G. Nagy M. Gacsi T. Röszer A. G. Basnakian article pmid16740394 Isotopic labeling of recombinant proteins expressed in the protozoan host Leishmania tarentolae 2006 Protein Expr. Purif. 48 167-172 2 A. Niculae P. Bayer I. C. Cirstea T. Bergbrede R. Pietrucha M. Gruen R. Breitling K. Alexandrov article pmid16612629 Phe-met-arg-phe (FMRF)-amide is a substrate source of NO synthase in the gastropod nervous system 2006 Cell Tissue Res. 325 567-575 3 T. Röszer E. Kiss-Toth M. Petko A. J. Szentmiklosi G. Banfalvi article pmid16502256 The neuropeptide FMRFamide can protect cells against apoptosis in the snail digestive gland 2006 Apoptosis 11 173-182 2 T. Röszer J. Kappelmayer G. G. Nagy A. J. Szentmiklosi A. G. Basnakian G. Banfalvi article pmid15697171 Molecular mechanisms of glucocorticoids in the control of inflammation and lymphocyte apoptosis 2005 Crit Rev Clin Lab Sci 42 71-104 1 J. P. Tuckermann A. Kleiman K. G. McPherson H. M. Reichardt article pmid14673196 A possible stimulatory effect of FMRFamide on neural nitric oxide production in the central nervous system of Helix lucorum L 2004 Brain Behav. Evol. 63 23-33 1 T. Röszer Z. Jenei T. Gall O. Nagy Z. Czimmerer Z. Serfozo K. Elekes G. Banfalvi article pmid15052467 Nitric oxide synthesis is blocked in the enteral nervous system during dormant periods of the snail Helix lucorum 2004 Cell Tissue Res. 316 255-262 2 T. Röszer Z. Czimmerer A. J. Szentmiklosi G. Banfalvi article pmid15033726 Early activation and induction of apoptosis in T cells is independent of c-Fos 2003 Ann. N. Y. Acad. Sci. 1010 225-231 H. Bierbaum S. Baumann I. Herr J. P. Tuckermann J. Hess M. Schorpp-Kistner P. Angel article pmid12034758 A role for endogenous glucocorticoids in wound repair 2002 EMBO Rep. 3 575-582 6 R. Grose S. Werner D. Kessler J. P. Tuckermann K. Huggel S. Durka H. M. Reichardt article pmid12082614 Calgranulins S100A8 and S100A9 are negatively regulated by glucocorticoids in a c-Fos-dependent manner and overexpressed throughout skin carcinogenesis 2002 Oncogene 21 4266-4276 27 C. Gebhardt U. Breitenbach J. P. Tuckermann B. T. Dittrich K. H. Richter P. Angel article pmid12815235 Development of the nitric oxide/cGMP system in the embryonic and juvenile pond snail, Lymnaea stagnalis L. A comparative in situ hybridization, histochemical and immunohistochemical study 2002 J. Neurocytol. 31 131-147 2 Z. Serfozo Z. Vereb T. Röszer G. Kemenes K. Elekes article pmid12464678 Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids 2002 J. Clin. Invest. 110 1729-1738 11 F. P. Limbourg Z. Huang J. C. Plumier T. Simoncini M. Fujioka J. P. Tuckermann G. Schutz M. A. Moskowitz J. K. Liao article pmid11375938 The collagen receptor DDR2 regulates proliferation and its elimination leads to dwarfism 2001 EMBO Rep. 2 446-452 5 J. P. Labrador V. Azcoitia J. P. Tuckermann C. Lin E. Olaso S. Manes K. Bruckner J. L. Goergen G. Lemke G. Yancopoulos P. Angel C. Martinez R. Klein article pmid11742993 Repression of inflammatory responses in the absence of DNA binding by the glucocorticoid receptor 2001 EMBO J. 20 7168-7173 24 H. M. Reichardt J. P. Tuckermann M. Gottlicher M. Vujić Spasić F. Weih P. Angel P. Herrlich G. Schutz article pmid11564170 Keratinocyte-specific onset of serine protease BSSP expression in experimental carcinogenesis 2001 J. Invest. Dermatol. 117 634-640 3 U. Breitenbach J. P. Tuckermann C. Gebhardt K. H. Richter G. Furstenberger G. Christofori P. Angel article pmid11776394 Expression of collagenase-3 (MMP-13) in c-fos-induced osteosarcomas and chondrosarcomas is restricted to a subset of cells of the osteo-/chondrogenic lineage 2001 Differentiation 69 49-57 1 J. P. Tuckermann R. Vallon S. Gack A. E. Grigoriadis D. Porte A. Lutz E. F. Wagner J. Schmidt P. Angel article pmid10893674 Collagenase-3 (MMP-13) and integral membrane protein 2a (Itm2a) are marker genes of chondrogenic/osteoblastic cells in bone formation: sequential temporal, and spatial expression of Itm2a, alkaline phosphatase, MMP-13, and osteocalcin in the mouse 2000 J. Bone Miner. Res. 15 1257-1265 7 J. P. Tuckermann K. Pittois N. C. Partridge J. Merregaert P. Angel article pmid11155788 Molecular genetic dissection of glucocorticoid receptor function in vivo 2000 Z Rheumatol 59 Suppl 2 1-5 H. M. Reichardt J. P. Tuckermann A. Bauer G. Schutz article pmid9989817 Both AP-1 and Cbfa1-like factors are required for the induction of interstitial collagenase by parathyroid hormone 1999 Oncogene 18 667-678 3 D. Porte J. P. Tuckermann M. Becker B. Baumann S. Teurich T. Higgins M. J. Owen M. Schorpp-Kistner P. Angel article pmid10613894 The DNA binding-independent function of the glucocorticoid receptor mediates repression of AP-1-dependent genes in skin 1999 J. 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