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，使儿童和成人易于骨折。大多数OI患者在编码1型胶原蛋白的两个基因之一中有突变。目前对OI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，这些疗法是有限的和不充分的。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（LRP 5）信号通路增强骨粘附导致两种OI小鼠模型的骨量和骨强度显著增加。在本申请中，我打算1）精确定义增强的LRP 5信号传导改善这些OI小鼠模型中的骨性质的机制，2）确定增强的LRP 5信号传导是否可以改善由于不同的1型胶原突变机制引起的其他OI小鼠模型中的骨性质，和3）测试产前施用抗硬化蛋白的中和性单克隆抗体，LRP 5的内源性抑制剂，与出生后抗sclerostin抗体治疗相比，能够进一步改善骨特性并提供针对免疫原性诱导的治疗抗性的保护。通过解决这些问题，我将确定增强LRP 5信号是否通过增加骨形成或通过改变OI成骨细胞分泌的基质蛋白的库来改善骨强度。我还将确定导致OI的突变类型是否决定了增强LRP 5信号传导对人类患者是有益还是有害。最后，使用小鼠OI模型，我将确定最佳改善骨特性的治疗策略，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.