The LRP5 Pathway and Osteoblast Function In Osteogenesis Imperfecta

成骨不全（OI）是一种遗传性疾病，其特征是骨量低， 儿童和成人骨折。大多数OI患者的两个基因中有一个发生突变， 编码1型胶原蛋白。目前针对OI患者的药物治疗是有限的，通过防止骨 在所有患者中，骨转换增加骨量，而不会降低骨折率。我们之前的研究表明 通过低密度脂蛋白受体相关蛋白5（LRP 5）信号传导增强骨粘附， 途径，或者通过增加信号传导的基因突变，或者通过施用结合 该途径的抑制剂，导致几种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，我们已经表明，成骨细胞从 OI小鼠的ER肿胀随着LRP 5信号的增加而改善，这表明蛋白质运输 提高了这是重要的，因为可获得增加LRP5信号传导和增强LRP5信号传导的疗法（硬化蛋白抗体）。 我们的数据表明，它们对OI患者有双重有益作用， 生产和改善成骨细胞功能。在本申请中，我们提出利用两种不同的 显性OI的小鼠模型1）为了鉴定Lrp5 HBM突变的分子机制， 改善OI的主要形式中I型胶原蛋白的蛋白运输，2）为了确定 硬化蛋白抗体治疗对成骨细胞发育和功能的影响，以及3）确定 在成骨细胞发育过程中需要增加的LRP 5信号传导以改善成骨细胞的功能， 主要的形式。这些目标的成功实现将使人们能够更好地了解 增加LRP 5信号传导既增加胶原蛋白产生又改善成骨细胞的机制 功能总之，这些结果将表明，靶向LRP 5信号传导的疗法与目前可用的其他疗法不同， 治疗不仅可以增加胶原蛋白的产生，还可以治疗成骨细胞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.