Targeting the Lrp5 Pathway To Increase Bone Strength In Osteogenesis Imperfecta

描述(由申请人提供)：遗传性疾病成骨不全(OI)的特征是骨量低，容易使儿童和成人发生骨骼骨折。大多数OI患者在编码1型胶原的两个基因中的一个发生突变。目前对OI患者的医学治疗大多是抗分解代谢，通过阻止骨转换来增加骨量。不幸的是，这些疗法是有限和不足的。在原理实验的证明中，我发现通过低密度脂蛋白受体相关蛋白5(LRP5)信号通路促进骨合成代谢，导致两种OI模型小鼠的骨量和骨强度显著增加。在本申请中，我打算1)精确定义LRP5信号增强改善这些OI小鼠模型骨属性的机制(S)，2)确定增强LRP5信号是否可改善由于不同的1型胶原突变机制引起的其他OI小鼠的骨属性，以及3)测试产前应用LRP5的内源性抑制物硬化素的中和性单抗是否能够进一步改善骨属性，并提供与生后抗硬化素抗体治疗相比，针对免疫原性诱导的治疗耐药性的保护。通过解决这些目标，我将确定增强LRP5信号是通过增加骨形成还是通过改变OI成骨细胞分泌的基质蛋白来提高骨强度。我还将确定导致OI的突变类型是否决定了增强LRP5信号将对人类患者有利还是有害。最后，使用小鼠OI模型，我将确定最好地改善骨骼特性同时将治疗副作用降至最低的治疗策略。

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.