Insights into Fracture Repair using a Murine Model of Osteofibrous Dysplasia

Osteofibrous dysplasia (OFD) is a rare disease characterized by the development of radiolucent lesions at the tibial periosteal surface, where it causes non-healing fractures. We previously identified gain-of-function mutations in the MET gene as a cause for OFD. Fracture tissue samples from OFD patients exhibit aberrant MET activity and delays in osteoblast differentiation. We hypothesized gain-of-function MET mutations result in delayed bone repair ability due to reduced osteoblast differentiation. MetΔ15-HET mice exhibit aberrant and prolonged upregulation of MET signaling and total β-catenin levels similar to OFD patients. MetΔ15-HET osteoblasts demonstrate a differentiation defect in vitro though no gross skeletal defects were identified. Fracture repair is delayed in MetΔ15-HET mice, with decreased bone formation 2-weeks post fracture-inducing surgery. Our data is consistent with a novel role for MET-mediated signaling regulating osteogenesis and open up the possibility of modulating the MET pathway to augment fracture healing.M.Sc