Fractures show delayed healing and increased possibility of re-fracture in OI murine models.

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Project Summary/Abstract Osteogenesis Imperfecta (OI) is the most common genetic bone dysplasia. It is characterized by bone deformities and fractures caused by low bone mass and impaired bone quality. Roughly 85-90% of cases are dominantly inherited and result from mutations in genes encoding type I collagen (COL1A1 and COL1A2), the major protein of the bone matrix. 10-15% of OI cases are recessively inherited and the majority result from mutations in members of the prolyl-3-hydroxylation complex including Cartilage Associated Protein (CRTAP). OI patients are at an increased risk of fracture throughout their lifetimes. Delayed healing and non-union has been reported in 24% of fractures and 52% of osteotomies in OI patients, higher than in the healthy population yet there have been few studies concerning the molecular mechanisms behind these healing abnormalities. Thus, there is an unmet need to better understand the mechanisms by which OI affects fracture healing. It is my goal to determine to what extent the fracture healing process differs in OI and how anti-TGFβ treatment may normalize or improve fracture healing and healed bone quality in murine models. I have observed a decrease in callus size and strength indicating a delay in fracture healing in Crtap–/– mice. It is my hypothesis that OI fractures undergo suboptimal healing and that this process results in ultimately weaker bone leading to the increased possibility of re-fracture. Using both Col1a2+/G610C and Crtap–/– mice (dominant and recessive models of OI, respectively), I will model long bone fracture healing using open tibial fracture surgery. I will determine the differences in OI fracture healing when compared to wild-type by collecting fractured tibia at multiple timepoints to observe fracture callus cartilage development and composition changes throughout the healing process. Additionally, I will analyze the architectural and biomechanical structure of the OI callus to determine the effect of the OI phenotype on the strength of healing/fully healed bone. Finally, our group demonstrated increased TGFβ signaling in OI bone using both Col1a2+/G610C and Crtap–/– OI mouse models that contributes to the low bone mass/quality phenotype. We further showed that anti-TGFβ treatment improves bone mass and quality in both OI mouse models. Therefore, I will investigate the effect of anti-TGFβ treatment on callus composition, callus strength, and healed bone strength/quality in OI and WT mice. Currently, anti-TGFβ anabolic treatments are in clinical trials yet their effect on fracture healing has not been assessed. Therefore, the knowledge gained from this study will be entirely novel and of high importance to the field of OI management. Furthermore, both Col1a2+/G610C and Crtap–/– mice model OI via mutations in collagen or collagen processing and the effect of extracellular matrix structure on fracture healing is poorly understood. By understanding fracture healing in OI, the results will have broad significance for basic fracture healing research. This proposal will not only confirm and elucidate abnormal healing in OI, it will also identify the mechanism behind these differences as well as assess the effect of a current therapy on the healing process.