The LRP5 Pathway and Osteoblast Function In Osteogenesis Imperfecta

成骨不全(OI)是一种以低骨量为特征的遗传性疾病，易患 儿童和成人都有骨性骨折。大多数OI患者的两个基因中的一个发生突变 编码1型胶原蛋白。目前对OI患者的药物治疗是有限的，通过预防骨骼起作用 翻转以增加骨量，而不降低所有患者的骨折发生率。我们之前的工作表明 通过低密度脂蛋白受体相关蛋白5(LRP5)信号促进骨合成代谢 途径，要么通过增加信号传递的基因突变，要么通过注射结合的抗体 该途径的抑制剂，导致几只小鼠的骨量和骨强度显著增加 由显性1型胶原突变引起的OI模型。此外，我们还表明，来自 OI小鼠的内质网肿胀随着LRP5信号的增加而改善，这表明蛋白质运输 是有改进的。这一点很重要，因为有治疗方法(硬化素抗体)可以增加LRP5信号和 我们的数据表明，它们对OI患者有双重益处，两者都能增加骨基质 产生和改善成骨细胞功能。在本应用程序中，我们建议使用两个不同的 1)显性OI小鼠模型以确定LRP5 HBM突变的分子机制 改善I型胶原在OI优势形式中的蛋白运输，2)确定 硬化素抗体对OI成骨细胞发育和功能的影响 在成骨细胞发育过程中需要增加LRP5信号来改善成骨细胞功能 OI的主要形式。这些目标的成功实现将使我们能够更好地理解 增加LRP5信号既促进胶原合成又促进成骨细胞的机制 功能。总而言之，结果将表明，与目前可用的其他疗法不同，针对LRP5信号的疗法 治疗，不仅增加胶原蛋白的产生，而且还治疗OI中出现的特定成骨细胞功能障碍， 这可能会为患者带来更好的结果。

Osteogenesis Imperfecta (OI) is a genetic disorder characterized by low bone mass that predisposes children and adults to skeletal fracture. Most patients with OI have a mutation in one of the two genes that encode type 1 collagen. Current medical therapies for patients with OI are limited, acting by preventing bone turnover to increase bone mass and do not decrease fracture rate in all patients. Our previous work has shown that enhancing bone anabolism via the low density lipoprotein receptor related-protein 5 (LRP5) signaling pathway, either through a genetic mutation that increases signaling or administration of an antibody that binds an inhibitor of the pathway, leads to significant increases in bone mass and bone strength in several mouse models of OI caused by dominant type 1 collagen mutations. In addition, we have shown that osteoblasts from mice with OI have ER swelling that improves with increased LRP5 signaling, suggesting that protein trafficking is improved. This is important as therapies (Sclerostin antibody) are available that increase LRP5 signaling and our data suggest they will be have dual beneficial effects in patients with OI, both increasing bone matrix production and improving osteoblast function. In the present application, we propose to utilize two different mouse models of dominant OI 1) To identify the molecular mechanisms by which an Lrp5 HBM mutation improves protein trafficking of type I collagen in dominant forms of OI, 2) To determine the effect of treatment with Sclerostin antibody on osteoblast development and function in OI and 3) To determine if increased LRP5 signaling is required during osteoblast development to improve osteoblast function in dominant forms of OI. The successful completion of these aims will allow for greater understanding of the mechanisms by which increased LRP5 signaling both increases collagen production and improves osteoblast function. Together the results will show that therapies targeting LRP5 signaling, unlike other currently available treatments, not only increase collagen production but also treat the specific osteoblast dysfunction seen in OI, which may lead to better outcomes for patients.