C2: Molecular mechanisms of glucocorticoid action during fracture healing after severe trauma

PIs: J. Tuckermann, A. Ignatius

Fracture healing is disturbed by additional blunt chest trauma, a condition present in severely injured patients. Chest trauma causes both, pulmonary and systemic inflammation. Glucocorticoids (GCs) released during a traumatic insult are potent suppressors of immune reactions. We previously showed that they control systemic and pulmonary inflammation via their GC receptor (GR) in myeloid cells by inducing anti-inflammatory genes, associated with alternative/anti-inflammatory macrophage activation. By limiting the systemic response GCs also participate in the resolution of local inflammation as they occur in fractures. In the inflammatory phase of fracture healing we showed that neutrophils are modulating the resolution of inflammation required to allow the subsequent repair process. We postulate that the local inflammation is shaped by GCs acting on neutrophils and macrophages. In turn, GCs have profound effects on chondrocytes and osteoblasts involved in callus formation and bone remodelling. Chondrocyte function is decisive for fracture callus formation and osteoblasts are essential for the remodelling and mineralisation. Therefore GCs likely modulate the repair and remodelling phases of fracture healing by unknown mechanisms. Our first data with a global GR deletion or lacking the GR specifically in chondrocytes indicate an attenuation of the healing process in the absence of GC-GR signaling. Moreover, we demonstrated that different modes of transcriptional mechanisms of GR are required for anti-inflammatory and bone modifying effects of GCs. GR-dimer dependent gene regulation acting in myeloid cells suppresses systemic inflammation and lung inflammation, whereas GR monomer action induces osteoporosis. In this project, we aim to elucidate how endogenous GCs released upon a blunt chest trauma influence the resolution of systemic inflammation by the GR in myeloid cells in the lung. We further address the modulation of local inflammation and subsequent repair process by GCs executed by GR in myeloid cells, chondrocytes and osteoblasts. We finally aim to clarify, how GR dimerisation and GR-momomer dependent modes of gene regulation modulate fracture healing. The anticipated results may help to develop strategies to optimise fracture healing after severe trauma.



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


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