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，可对许多美国人造成衰弱影响。 老兵据估计，4400万美国人，即50岁及以上人口的55%， 目前有骨折的危险改善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。拟议 研究利用导致非常高的骨量的人类疾病。这些高血压的遗传原因 骨质量疾病--颅管骨质增生、硬化症、货车Buchem病--提供了对 如何控制骨质疏松患者的骨量，以改善他们的骨骼健康， 骨折许多与高骨量相关的疾病是由细胞信号传导的突变引起的 称为“Wnt”的途径因此，Wnt通路的操纵对骨骼健康有很大的希望 改进.该途径作为治疗靶点特别有吸引力，因为它可以被操纵以 增加新骨的形成，而不是简单地防止进一步的骨质流失（这是为什么所有的，但其中之一， 目前可用的FDA批准的疗法起作用）。拟议项目的长期目标有两个方面： 首先，我们试图理解分泌的Wnt信号传导抑制剂如何作为协调单位发挥作用（即，一 环境），通过在调节该单元的其它成员时调节它们的表达水平（例如，抑制或 删除）。欧盟成员国在表达方面的这些调整是主要目标 机会，制定大的变化，在骨合成代谢行动，因为我们的支持数据表明。我们还寻求 为了了解这种Wnt抑制剂环境如何控制机械负荷的合成代谢作用， 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 抑制性环境起到“归巢信号”作用，以确保新骨被添加到最需要的地方- 在骨的高应变区域，并且在不需要的地方不添加-在低应变区域 的骨头。我们的数据再次表明，Wnt抑制环境在这一过程中起着重要作用。我们 本申请的第二个目标是进行针对Wnt抑制剂环境的功能研究，其具有直接的 适用于患者的未来治疗方法。骨消耗状况，如机械废用 (e.g.,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） 在退伍军人中很常见。根据我们和其他人对 在废用和糖皮质激素暴露后Wnt抑制剂表达的变化，我们假设 四个Wnt通道-Sost、Dkk 1、sFrp 4和Wise的“补偿环境”-通过未知的 机制，以防止合成代谢作用的存在下，废用糖皮质激素治疗。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性 暴露在这些骨质流失的环境中如果是这样的话，这些研究将对人类产生深远的影响。 设计旨在治疗废用性和糖皮质激素引起的骨质疏松的退伍军人的疗法。 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， 为了确定我们是否可以减少产生显著的免疫应答所需的Sost抗体的剂量/体积， 通过额外阻断作为代偿环境一部分的辅助Wnt抑制剂来抑制合成代谢反应。 我们已经表明，如果我们将Dkk 1抗体用于 Sost抑制的存在。我们预期使用低得多的剂量， 如果我们同时阻断其他辅助性Wnt抑制剂，我们就可以获得抗Wnt抗体。在这一更新Merit应用程序中，我们 解决这些问题，以确定改善退伍军人群体骨骼健康的新方法， 以及广大公众。

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.