Targeting the Lrp5 Pathway To Increase Bone Strength In Osteogenesis Imperfecta

描述（由申请人提供）：成骨不全症（Osteogenesis Imperfecta， OI）是一种遗传性疾病，其特征是骨量低，易使儿童和成人发生骨骨折。大多数成骨不全患者编码1型胶原蛋白的两个基因中的一个发生突变。目前对成骨不全患者的医学治疗主要是抗分解代谢，通过阻止骨转换来增加骨量。不幸的是，这些治疗方法是有限和不充分的。在原理证明实验中，我发现通过低密度脂蛋白受体相关蛋白5 （LRP5）信号通路增强骨合成代谢可导致两种成骨不全小鼠模型的骨量和骨强度显著增加。在目前的申请中，我打算1)精确定义增强的LRP5信号改善这些成骨不全小鼠模型中的骨特性的机制，2)确定增强的LRP5信号是否可以改善由于不同的1型胶原突变机制导致的其他成骨不全小鼠模型中的骨特性，以及3)测试产前给药抗内源性LRP5抑制剂硬化蛋白的中和性单克隆抗体，与出生后抗硬化蛋白抗体治疗相比，能够进一步改善骨特性，并提供免疫原性诱导的治疗抵抗保护。通过解决这些目标，我将确定增强LRP5信号是否通过增加骨形成或改变成骨成骨细胞分泌的基质蛋白库来提高骨强度。我还将确定导致成骨不全的突变类型是否决定了增强LRP5信号传导对人类患者是有益还是有害。最后，使用小鼠成骨不全模型，我将确定治疗策略，最好地改善骨特性，同时最大限度地减少治疗的副作用。

DESCRIPTION (provided by applicant): The genetic disorder Osteogenesis Imperfecta (OI) is 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 mostly anti-catabolic, acting by preventing bone turnover to increase bone mass. Unfortunately, these therapies are limited and inadequate. In proof of principle experiments, I have found that enhancing bone anabolism via the low density lipoprotein receptor related-protein 5 (LRP5) signaling pathway leads to significant increases in bone mass and bone strength in two mouse models of OI. In the present application, I intend 1) to precisely define the mechanism(s) by which enhanced LRP5 signaling improves bone properties in these mouse models of OI, 2) to determine whether enhanced LRP5 signaling can improve bone properties in other mouse models of OI that are due to different type 1 collagen mutational mechanisms, and 3) to test whether prenatal administration of a neutralizing monoclonal antibody against sclerostin, an endogenous inhibitor of LRP5, is able to effect further improvements in bone properties and provide protection against immunogenicity-induced treatment resistance in comparison to postnatal anti-sclerostin antibody therapy. By addressing these aims, I will determine whether enhancing LRP5 signaling improves bone strength by increasing bone formation or by altering the repertoire of matrix proteins that are secreted by OI osteoblasts. I will also identify whether the type of mutation that causes OI determines whether enhancing LRP5 signaling will be beneficial or detrimental to human patients. Finally, using a mouse OI model, I will identify therapeutic strategies that best improve bone properties while minimizing the side effects of therapy.