Harnessing the anabolic potential of Wnt signaling to improve bone health

骨质疏松症(多孔性骨病)是一种骨骼疾病，可对许多美国人产生衰弱作用 退伍军人。据估计，有4400万美国人，即55%的50岁及以上的人， 目前有骨质疏松性骨折的风险。改善这种疾病的治疗方案需要更大的 了解控制骨代谢的细胞事件和信号通路。建议数 研究利用了导致骨量非常高的人类疾病。这些高的遗传原因 骨量疾病--颅管骨质增生症、硬化症、范布赫姆病--提供了对 如何控制骨质疏松症患者的骨量以改善其骨骼健康并预防 骨折。许多与高骨量相关的疾病是由细胞信号突变引起的。 一条叫做“Wnt”的小路因此，对Wnt通路的操纵对骨骼健康大有可为 进步。这一途径作为治疗靶点特别有吸引力，因为它可以被操纵来 促进新骨形成，而不是简单地防止进一步的骨丢失(这是除一种以外的所有 目前可用的FDA批准的疗法有效)。拟议项目的长期目标有两个： 首先，我们试图了解分泌的Wnt信号抑制物如何作为一个协调单位发挥作用(即，一个 环境)，通过在该单元的其他成员被调整时调整它们的表达水平(例如，禁止或 删除)。环境成员在表达上的这些调整代表了主要的目标 正如我们的支持数据所表明的那样，有机会在骨骼的合成代谢活动中产生巨大的变化。我们还在寻求 为了了解这种Wnt抑制剂环境是如何控制机械负荷的合成代谢作用的--一种有效的 对骨骼有持久益处的合成代谢刺激。我们试图了解某些成员是否 抑制环境的作用就像“归巢信号”，确保新的骨骼被添加到最需要它的地方- 到骨骼的高应变区域，而不是在不需要的地方添加它-到低应变区域 在骨头上。我们的数据再次表明，Wnt抑制环境在这一过程中发挥着重要作用。我们的 该应用程序的第二个目标是针对Wnt抑制剂环境进行功能研究，这些环境具有直接的 对患者未来治疗方法的适用性。骨损耗情况，如机械性废弃 (例如，卧床休息、瘫痪)和糖皮质激素治疗(一种用于治疗炎症和免疫的药物)。 镇压)在退伍军人中很常见。基于我们和其他人对 停用和糖皮质激素暴露后Wnt抑制物表达的变化，我们假设 四种Wnt抑制剂--SOST、Dkk1、sFRP4和Wise的“代偿环境”--通过未知途径协调 在停用糖皮质激素治疗的情况下防止合成代谢作用的机制。我们建议 以不同的组合针对整个环境，以确定我们是否可以恢复小鼠的合成代谢活动 暴露在这些骨质流失的条件下。如果是这样的话，这些研究将对 旨在治疗退伍军人因停用和糖皮质激素导致的骨缺乏症的疗法设计。 我们将进行的另一项功能研究也利用了Wnt抑制剂环境的生物学，是 为了确定我们是否可以减少SOST抗体的剂量/体积，以产生显著的 合成代谢反应是通过额外阻断作为代偿环境一部分的辅助Wnt抑制剂来实现的。 我们已经证明，如果我们将Dkk1抗体用于治疗，我们可以显著提高它的合成代谢效率 SOST抑制的存在。我们预计使用低得多的剂量的 如果我们同时阻断其他辅助的Wnt抑制物，就会产生抗体。在此续订奖励申请中，我们 解决这些问题，以确定在退伍军人中改善骨骼健康的新方法， 以及在普通公众中。

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 human diseases that result in very high bone mass. The genetic causes of these high bone mass diseases—craniotubular hyperostosis, sclerosteosis, van Buchem's disease—provide insight into how bone mass can be manipulated in osteoporotic patients to improve their skeletal health and prevent fractures. Many of the high-bone-mass associated diseases are caused by mutations in a cell signaling pathway called “Wnt.” Thus, manipulation of the Wnt pathway holds great promise for skeletal health improvement. This pathway is particularly attractive as a therapeutic target because it can be manipulated to increase new bone formation, rather than simply prevent further bone loss (which is how all but one of the currently available FDA-approved therapies work). The long term goals of the proposed project are twofold: first, we seek to understand how the secreted inhibitors of Wnt signaling function as a coordinated unit (i.e., a milieu), by adjusting their expression levels when other members of the unit are adjusted (e.g., inhibited or deleted). Those adjustments in expression in the members of the milieu represent prime targeting opportunities to enact large changes in anabolic action in bone, as our supporting data suggest. We also seek to understand how this Wnt inhibitor milieu controls the anabolic action of mechanical loading—a potent anabolic stimulus that has lasting benefits to the skeleton. We seek to understand whether certain members of the inhibitory milieu function as “homing signals” to ensure that new bone is added where it is needed most – to the high strain regions of the bone, and that it is not added where it is not needed – to the low strain regions of the bone. Again, our data suggest that the Wnt inhibitory milieu plays a significant role in this process. Our second goal of the application is to conduct functional studies targeting the Wnt inhibitor milieu, that have direct applicability to future therapeutic approaches in patients. Bone wasting conditions such as mechanical disuse (e.g., bedrest, paralysis) and glucocorticoid therapy (a drug used for treating inflammation and immuno- suppression) are common among veterans. Based on measurements we and others have made regarding the changes in expression of Wnt inhibitors following disuse and glucocorticoid exposure, we hypothesize that the “compensatory milieu” of four Wnt inhibitors–Sost, Dkk1, sFrp4, and Wise—coordinate via unknown mechanisms to prevent anabolic action in the presence of disuse glucocorticoid therapy. We propose to target the entire milieu in different combinations, to determine whether we can restore anabolic activity in mice exposed to these bone wasting conditions. If so, those studies would have far-reaching implications for the design of therapies aimed at treating veterans with disuse- and glucocorticoid-induced bone deficiencies. Another functional study we will undertake, which also capitalizes on the biology of the Wnt inhibitor milieu, is to determine whether we can reduce the dose/volume of Sost antibody required to generate a significant anabolic response by additionally blocking accessory Wnt inhibitors that are part of the compensatory milieu. We have already shown that we can dramatically increase the anabolic efficacy of Dkk1 antibody if we use it in the presence of Sost inhibition. We anticipate a significant osteoanabolic effect using much lower doses of antibody if we simultaneously block other accessory Wnt inhibitors. In this renewal Merit application, we address these questions in order to identify new ways to improve bone health among the veteran population, and among the public in general.