Improving bone health by harnessing the anabolic potential of LDL receptor relate

描述(由申请人提供)： 骨质疏松症(多孔性骨病)是一种骨骼疾病，可能会使许多美国退伍军人虚弱。据估计，美国有4400万人，占50岁及以上人口的55%，目前面临骨质疏松性骨折的风险。改善这种疾病的治疗方案需要更多地了解控制骨代谢的细胞事件和信号通路。这项拟议的研究利用了最近在几个人类家族中发现的低密度脂蛋白受体相关蛋白5(LRP5)2-螺旋桨1的一系列错义突变，这些突变对骨量调节有重大影响。拟议项目的长期目标是识别新的分子靶点，这些靶点来自利用这些突变设计的新型小鼠模型，用于药物干预，旨在改善骨量和降低骨折易感性。在体外，LRP5被认为参与了典型的WNT信号级联(例如，GSK32介导的2-连环蛋白活性的调节)，但我们最近的数据表明，经典WNT信号的变化可能不能解释HBM突变的合成代谢效应。LRP5控制骨形成的机制的发现将带来改善骨量的新方法。在这个应用中，我们建议确定LRP5的骨形成效应是否需要2-连环蛋白。我们将使用两种新的HBM病敲入小鼠模型。这些小鼠是以两个LRP5 HBM人类家族为模型的，它们的G171V或A214V氨基酸替换敲入了LRP5。这些突变导致非常高的骨量，完全由骨形成增加驱动，而骨吸收没有变化。我们将测试当2-连环蛋白缺失时，这两个突变是否与骨形成增加有关。此外，我们将确定LRP5基因敲除小鼠的骨形成表型是否可以通过2-连环蛋白的结构性激活来挽救。随后，我们将确定G171V和A214V突变的作用机制，这两种突变在细胞和组织水平上似乎具有根本不同的影响。在这个优点应用中，我们解决这些问题，以确定新的与LRP5相关的合成代谢靶点，以改善骨骼健康。 公共卫生相关性： 大约25%的50岁以上的男性在老年时会遭受骨质疏松性骨折，髋部骨折后的一年死亡率几乎是男性的2W。髋部骨折前能活动的患者中，有五分之一在骨折后需要长期护理。除了他们的年龄，其他生活方式因素使退伍军人特别容易患上骨质疏松症，包括吸烟、饮酒和缺乏运动。此外，许多越战老兵在战争期间暴露在环境因素中，例如二恶英TCDD(在橙剂中发现)，这使他们面临更大的骨质疏松风险。最近，退伍军人管理局修改了其裁决规则，为被拘留或拘留至少30天的前战俘(POW)以及最近被诊断患有创伤后应激障碍(PTSD)、其骨质疏松至少有10%残疾的人建立了骨质疏松症的服务联系推定。显然，有必要为患有低骨量疾病的退伍军人确定新的治疗方案。

DESCRIPTION (provided by applicant): Osteoporosis (porous bone disease) is a disease of the skeleton that can have debilitating effects on many US veterans. An estimated 44 million Americans, or 55 percent of the people 50 years of age and older, are currently at risk for osteoporotic fracture. Improved treatment options for the disease require a greater understanding of the cellular events and signaling pathways that control bone metabolism. The proposed research capitalizes on a collection of missense mutations in 2-propeller 1 of the LDL-receptor-related protein 5 (LRP5), recently identified in several human families, that have a major impact on bone mass regulation. The long term goal of the proposed project is to identify new molecular targets, yielded from novel mouse models engineered with those mutations, for pharmacologic intervention aimed at improving bone mass and reducing fracture susceptibility. LRP5 has been postulated to participate in the canonical WNT signaling cascade (e.g., GSK32-mediated modulation of 2- catenin activity) in vitro, but our recent data indicates that alterations in canonical WNT signaling might not account for the anabolic effects of the HBM mutations. Discovery of the mechanism by which Lrp5 controls bone formation would lead to new approaches for improving bone mass. In this application, we propose to determine whether 2-catenin is required for the bone formation effects of Lrp5. We will use two novel knock-in mouse models of HBM disease. These mice, which are modeled after two of the LRP5 HBM human families, have either the G171V or the A214V amino acid substitutions knocked in to Lrp5. The mutations result in very high bone mass, driven completely by increased bone formation, with no change in bone resorption. We will test whether these two mutations are associated with increased bone formation when 2- catenin is deleted. Further, we will determine whether the bone formation phenotype of Lrp5 knockout mice can be rescued by constitutive activation of 2-catenin. Subsequently, we will determine the mechanism of action for the G171V and A214V mutations, which appear to have fundamentally different effects at the cellular and tissue levels. In this Merit application, we address these questions in order to identify new Lrp5-associated anabolic targets for improving bone health. PUBLIC HEALTH RELEVANCE: Roughly 25% men over the age of 50 will suffer an osteoporotic fracture during their senior years, and the 1- year mortality rate following a hip fracture is nearly 2W as high for men as for women. One-fifth of those who were ambulatory before their hip fracture require long-term care afterward. Beyond their age, other lifestyle factors make veterans particularly susceptible to osteoporosis, including smoking, alcohol consumption, and an inactivity. Moreover, many Vietnam veterans were exposed to environmental factors during the war, such as the dioxin TCDD (found in Agent Orange), which put them at much greater risk for osteoporosis. Recently, the VA amended its adjudication regulation to establish a presumption of service connection for osteoporosis for former Prisoners of War (POWs) who were detained or interned for at least 30 days, and more recently, for those diagnosed with posttraumatic stress disorder (PTSD), and whose osteoporosis is at least 10% disabling. There is a clear need to identify new treatment options for veterans that suffer from low bone mass disease.