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, refractures typically go unreported, making the frequency of refractures 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 ^G610c/+ 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 with the contralateral unfractured bone, suggesting that abnormal OI fracture healing OI may prime future refracture at the same location. We have previously shown upregulated 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. © 2020 American Society for Bone and Mineral Research.

中文翻译：

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与成骨不全的胶原相关的临床前模型中的骨折愈合。

成骨不全症（OI）是遗传性骨发育不良，其特征是由于骨量低和骨骼质量受损而导致的骨畸形和骨折。OI是一种遗传异质性疾病，最常见的原因是编码I型胶原的基因（COL1A1和COL1A2）。此外，OI是隐性遗传的，大多数情况是由脯氨酰3-羟基化复合物成员的突变引起的，其中包括软骨相关蛋白（CRTAP）。OI患者一生中骨折的风险增加。但是，据报道有24％的骨折和52％的截骨术不愈合或延迟愈合。另外，通常没有报道骨折的发生，使得OI患者的骨折发生频率未知。因此，亟需更好地了解OI影响骨折愈合的机制。使用开放式胫骨骨折模型，我们的研究表明Col1a2 ^{G610c / +}和Crtap ^-/-的愈合均延迟 OI小鼠模型（分别为显性和隐性OI）与减少的愈伤组织大小和预测的强度有关。OI中的愈伤组织软骨分布和软骨细胞成熟发生改变，表明软骨分化加速。重要的是，我们确定与对侧未骨折骨相比，雌性OI小鼠中愈合的胫骨骨折在生物力学上较弱，这表明异常的OI骨折愈合OI可能会在同一位置引发未来的骨折。我们以前在OI中显示出TGF-β信号转导上调，并在骨折愈合的情况下证实了这一点。有趣的是，对Crtap ^-/-的处理 含有抗TGF-β抗体1D11的小鼠可进一步减小愈伤组织的大小，并能预测强度，这突出了研究治疗策略中剂量反应的重要性。这些数据为了解细胞外基质（ECM）对骨折愈合的作用提供了有价值的见解，人们对此机制了解甚少，并支持预防原发性骨折以减少OI患者的骨折和畸形发生率的需求。©2020美国骨骼和矿物质研究学会。