Stress associated glucocorticoid hormones in immune system and bone integrity
- molecular mechanisms and regulators of bone homeostasis
- hormonal control and regulation of inflammation
Corticosteroid hormones are major determinants of the stress response, circadian rhythm and regulate metabolic, immunologic and tissue homeostatic processes. They are frequently used for the treatment of inflammatory diseases such as rheumatoid arthritis or asthma. Despite the beneficial effects of repressing inflammation, steroid therapy has severe side effects on bone (osteoporosis) and metabolism.
Our aim is to unravel the underlying mechanism of steroid action in different cell-types and how these contribute to the beneficial effects, or side effects of glucocorticoids in different diseases.
We made major contributions to identify the cell-type specific molecular mechanisms of cortiosteroids for beneficial steroid therapy.
With the help of conditional and function-selective knockout mice for the glucocorticoid receptor (GR), the lab identified critical cell types and novel mechanisms for anti-inflammatory activities of glucocorticoids in different inflammatory disease mouse models (Vettorazzi et al. Nat Comm (2015), Lim et al. Genome Research (2015), Kleiman et al. FASEB J (2012), Vandevyver et al. J Clin Inv (2012), Baschant et al. PNAS (2011), Tuckermann et al. J Clin Inv (2007), Reichardt et al. EMBO J (2001), Tuckermann et al. J Cell Biol (1999), Reichardt et al. Cell (1998)).
In a model of lung inflammation we made the amazing discovery that beneficial anti-inflammatory actions of glucocorticoids are not dependent on the inhibition of pro-inflammatory mediators. During inflammation however, glucocorticoid action requires cooperation with pro-inflammatory signaling pathways (e.g. p38) to induce anti-inflammatory genes and alternative polarization of macrophages (Vettorazzi et al. Nat Comm (2015)).
To unravel the molecular mechanisms of glucocorticoid action on bone integrity and to identify new regulators of bone homeostasis, we developed high-throughput screening tools. Our aim is to unravel novel regulators of osteoblast differentiation, proliferation and transformation to get novel rationales for improved therapies of osteoporosis and bone tumors. Translating our new findings in transgenic mouse models will prove the respective relevance in vivo. Furthermore, with the help of CRISPR/Cas-system we aim to validate our novel regulators of bone integrity in the human system.
To accomplish the goals of our research we use a broad range of state-of-the-art techniques: cell biological and molecular biological techniques, viral gene delivery as well as histological methods, lineage tracing and micro computer tomography measurements in conditional knock out mice.
Zeynab Najafova, Peng Liu , Florian Wegwitz, Mubashir Ahmad, Liezel Tamon, Robyn Laura Kosinsky, Wanhua Xie, Steven A Johnsen, Jan Tuckermann (2020) RNF40 exerts stage-dependent functions in differentiating osteoblasts and is essential for bone cell crosstalk. Cell Death Differ. doi: 10.1038/s41418-020-00614-w.
Pfänder P, Fidan M, Burret U, Lipinski L, Vettorazzi S (2019) Cdk5 Deletion Enhances the Anti-inflammatory Potential of GC-Mediated GR Activation During Inflammation. Front. Immunol. https://doi.org/10.3389/fimmu.2019.01554
Koenen M, Culemann S, Vettorazzi S, Caratti G, Frappart L, Baum W, Krönke G, Baschant U, Tuckermann JP (2018) Glucocorticoid receptor in stromal cells is essential for glucocorticoid-mediated suppression of inflammation in arthritis. Ann Rheum Dis. 77(11):1610-1618
Lee S, Liu P, Teinturier R, Jakob J, Tschaffon M, Tasdogan A, Wittig R, Hoeller S, Baumhoer D, Frappart L, Vettorazzi S, Bertolino P, Zhang C, Tuckermann J (2018) Deletion of Menin in craniofacial osteogenic cells in mice elicits development of mandibular ossifying fibroma. Oncogene 37(5):616-626
Vettorazzi S, Bode C, Dejager L, Frappart L, Shelest E, Klassen C, Tasdogan A, Reichardt HM, Libert C, Schneider M, Weih F, Henriette Uhlenhaut NH, David JP, Graler M, Kleiman A and Tuckermann JP (2015) Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1. Nat Commun 6:7796
more publications from Prof. Dr. Jan Tuckermann can be found in our list of publications.
Dr. Mubashir Ahmad (Postdoc), Michael Burret (Technical Assistent), Ute Burret (Technical Assistent), Dr. Giorgio Caratti (Postdoc), Bozhena Caratti (PhD-Student) Jennifer Laufer (Secretary), Ulrike Kelp (Technical Assistent), Dr. Merle Stein (Postdoc), Prof. Dr. Jan Tuckermann (Director, Group Leader), Dr. Sabine Vettorazzi (Postdoc), Anna Weiss (Lab Assistant), Dr. Stephanie Wittig-Blaich (Postdoc), Dr. Sooyeon Lee (Postdoc), Kevin Paxian (PhD-Student), Jonathan Preuß (PhD-Student), Ulrich Stifel (PhD-Student), Denis Nalbantoglu (PhD-Student)