C2: Cell type specific mechanisms of glucocorticoid action during fracture healing after severe trauma

PIs: J. Tuckermann, A. Ignatius

During the first funding period, we investigated how glucocorticoids (GC) and their cognate receptor, the GR, a nuclear hormone receptor, regulate the inflammatory response and bone regeneration in regular and compromised fracture healing induced by a concomitant injury. We demonstrated that the GR is generally required for endochondral bone formation. GR dimerization is essential for the anti-inflammatory effects of GC, and polarizes macrophages towards an anti-inflammatory phenotype via cell autonomous and non- autonomous effects. Here, the GR cooperates with pro-inflammatory signaling. Surprisingly, when the fracture was combined with a thoracic trauma, we showed that impaired GR dimerization rescues mice from trauma- induced compromised bone repair. Finally, by a functional screen in osteoblasts, we identified novel drug targets that overcome the deleterious glucocorticoid effects on bone mass. In the second funding period, we aim to identify the progenitor cells, which are responsible for disturbed cartilage-to-bone transition during fracture healing by using lineage tracing. We will decipher how exogenous GCs modulate fracture healing and whether compounds overcoming GC effects on bone improve bone repair. Further, we aim to unravel the deleterious effects of GR dimerization in trauma-induced compromised fracture healing, by dissecting the cell-autonomous and cell-non-autonomous effects of the GR on macrophage skewing, transcriptomics and cellular metabolism with focus on the lung tissue. We expect to unravel the cell type specific action and molecular base of one of the major stress response hormones, the GC, during the trauma response.

Projektleiter

Prof. Dr. Jan Tuckermann
Universität Ulm
Institut für Allgemeine Zoologie und Endokrinologie 
Helmholtzstr. 8/1
89081 Ulm
Tel.: +49 731 500 32600
Fax: +49 731 500 32609
jan.tuckermann(at)uni-ulm.de

 

Prof. Dr. Anita Ignatius
Institut für Unfallchirurgische Forschung und Biomechanik
Zentrum für Traumforschung Ulm
Universitätsklinikum Ulm
Helmholtzstr. 14
89081 Ulm
Tel.: +49 731 500 55301
Fax: +49 731 500 55302
anita.ignatius(at)uni-ulm.de
www.biomechanics.de