Harnessing the anabolic potential of Wnt signaling to improve bone health

骨质疏松症（多孔性骨疾病）是一种骨骼疾病， 对许多美国退伍军人的影响。估计有4400万美国人， 50岁及以上，目前有骨质疏松性骨折的风险。改进的治疗 治疗这种疾病的方法需要更深入地了解细胞事件和信号传导， 控制骨代谢的途径。拟议的研究利用了最近 鉴定了Wnt糖蛋白的分泌抑制剂。拟议项目的长期目标是 研究靶向一种新的分泌型Wnt信号抑制剂Notum是否能改善 骨特性和降低骨折易感性。在第一个目标中，我们建议确定 Notum抑制通过交叉作用对骨稳态发挥作用的细胞类型 条件Notum突变小鼠对不同的Cre驱动程序，这些驱动程序在不同的阶段是活跃的。 间充质细胞谱系。我们还将观察由细胞因子诱导的基因表达变化。 Notum抑制，以观察经典Wnt通路、非经典Wnt通路、 Hedgehog途径或其他途径主要受到影响。我们还将确定 Notum抑制改变的通路中的下游节点，看看是否有更容易 Notum抑制诱导的HBM表型的靶向效应物。第二个目标，我们 将针对Notum进行功能研究，该研究可直接适用于未来 患者的治疗方法。糖皮质激素在退伍军人中广泛使用 人口的许多条件，包括器官移植，类风湿性关节炎， 炎症性肠病和其他疾病，但副作用并不小，骨消耗是一个 糖皮质激素治疗患者的主要问题。同样，机械废弃是一个主要的 退伍军人中的问题，这是由于长期卧床，瘫痪，和其他 并发症我们将在这些临床前模型中抑制Notum，以确定Notum是否 抑制代表了在两个相关阶段中保留骨量和功能的可行策略， 骨质疏松症在此更新Merit应用程序中，我们按顺序解决这些问题 找出改善退伍军人骨骼健康的新方法， 公众一般。

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 recently identified secreted inhibitor of Wnt glycoproteins. The long-term goal of the proposed project is to investigate whether targeting a new, secreted inhibitor of Wnt signaling—Notum--can improve bone properties and reduce fracture susceptibility. In the first aim we propose to determine the cell type in which Notum inhibition exerts its effects on bone homeostasis, by crossing conditional Notum mutant mice to different Cre drivers that are active during different stages of the mesenchymal cell lineage. We will also look the gene expression changes induced by Notum inhibition to see if the canonical Wnt pathway, the noncanonical Wnt pathway, the Hedgehog pathway, or some other pathway, is primarily affected. We will also identify downstream nodes in the pathways altered by Notum inhibition, to see if there are more readily targetable effectors of the HBM phenotype induced by Notum inhibition. I the second aim, we will conduct functional studies targeting Notum, which has direct applicability to future therapeutic approaches in patients. Glucocorticoids are widely used among the veteran population for numerous conditions, including organ transplant, rheumatoid arthritis, inflammatory bowel disease, and others, but side effects are not trivial, and bone wasting is a major concern among glucocorticoid-treated patients. Likewise, mechanical disuse is a major problem among veterans, which results from long term bedrest, paralysis, and other complications. We will inhibit Notum in these preclinical models to determine whether Notum inhibition represents a viable strategy for preserving bone mass and function during two relevant bone wasting conditions. 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.