Mechanisms of Integrin α2β1 driven cell-matrix interaction in the course of bone regeneration and fracture healing

• Applicant: Professor Dr. Richard Stange
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 437825722

Integrins, a well characterized family of heterodimeric cell adhesion and signal transduction proteins, serve as receptors, focal adhesion components and transducers of mechanical signals. Integrin α2β1 is the major receptor for fibrillary collagens in bone. Recently we could show that in the absence of this protein bone forming cells are primed to produce more matrix i.e. collagen type I which alleviates the effects of age related bone degradation. To transfer this to a clinical problem, we want to investigate the role of integrin α2β1 in fracture repair. In preliminary studies we could demonstrate that 7 days after fracture healing in the integrin α2β1 deficient bone appears to be more advanced. The fracture callus is further developed, and we could detect more overall collagen in the fracture callus. The aim of this project is to determine whether the accelerated fracture repair continues to the overall clinical outcome. Further investigations will elucidate the molecular mechanisms which are involved in the integrin α2β1 dependent over-expression of collagen type I. Therefore we will investigate a well-known pathway involved in expression of collagen and bone matrix, the TGFβ and accordingly the BMP-pathway. This will be done by in-vitro analyzation of the expression of collagen and bone target genes under inhibition of either TGF-β or BMP. Finally we will translate these findings into clinical application by exogenous inhibition of integrin α2β1 in vitro as well as in vitro. As effector we have chosen rhodocetin, a potent and stable compound of snake venom with highly specific integrin α2β1 inhibition as well as an alternative approach with integrin α2β1 blocking antibody. Improving the outcome of fracture repair by these investigations could be a novel therapeutic approach to treat osteoporotic and non-healing fractures.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Johannes Andreas Eble