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Fracture healing in collagen-related preclinical models of Osteogenesis Imperfecta.

07:00 EST 13th February 2020 | BioPortfolio

Summary of "Fracture healing in collagen-related preclinical models of Osteogenesis Imperfecta."

Osteogenesis Imperfecta (OI) is a genetic bone dysplasia characterized by bone deformities and fractures caused by low bone mass and impaired bone quality. OI is a genetically heterogeneous disorder that most commonly arises from dominant mutations in genes encoding type-I collagen (COL1A1 and COL1A2). In addition, OI is recessively inherited with the majority of cases resulting from mutations in prolyl-3-hydroxylation complex members, which includes Cartilage Associated Protein (CRTAP). OI patients are at an increased risk of fracture throughout their lifetimes. However, non-union or delayed healing has been reported in 24% of fractures and 52% of osteotomies. Additionally, re-fractures typically go unreported making the frequency of re-fractures in OI patients unknown. Thus, there is an unmet need to better understand the mechanisms by which OI affects fracture healing. Using an open tibial fracture model, our study demonstrates delayed healing in both Col1a2 and Crtap OI mouse models (dominant and recessive OI, respectively) that is associated with reduced callus size and predicted strength. Callus cartilage distribution and chondrocyte maturation were altered in OI suggesting accelerated cartilage differentiation. Importantly, we determined that healed fractured tibia in female OI mice are biomechanically weaker when compared to the contralateral unfractured bone suggesting that abnormal OI fracture healing OI may prime future re-fracture at the same location. We have previously shown up-regulated TGF-β signaling in OI and we confirm this in the context of fracture healing. Interestingly, treatment of Crtap mice with the anti-TGF-β antibody, 1D11 resulted in further reduced callus size and predicted strength, highlighting the importance of investigating dose response in treatment strategies. These data provide valuable insight into the effect of the extracellular matrix (ECM) on fracture healing, a poorly understood mechanism, and support the need for prevention of primary fractures to decrease incidence of refracture and deformity in OI patients. This article is protected by copyright. All rights reserved.

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This article was published in the following journal.

Name: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
ISSN: 1523-4681
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