Mechanisms of WNT Signaling in Bone

骨中 WNT 信号传导机制

基本信息

批准号：
8305431
负责人：
Fanxin Long
金额：
$ 38.96万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-20 至 2015-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Wnt signaling provides a promising target pathway for developing novel bone anabolic agents. Most studies to date have supported a model in which autocrine or paracrine Wnt signaling in osteoblast-lineage cells directly controls osteoblast biology. This model however, was challenged by a recent study that concluded that LRP5, a co-receptor for Wnt proteins, does not function directly in osteoblasts, but rather through regulating enteric production of serotonin. This study therefore has cast uncertainty about the physiological relevance of direct Wnt signaling in bone. A major cause for the uncertainty is that genetic deletion of ¿-catenin (an obligatory effector of canonical Wnt signaling) in osteoblasts by 2.3Col1-Cre did not affect osteoblast number or function in postnatal animals. However, previous work in the mouse embryo indicates that Wnt/Lrp5/¿-catenin signaling may function at a stage before 2.3Col1-Cre becomes active. Directly testing this notion in postnatal life has not been feasible because of the lack of proper genetic tools. We have now developed a novel Tet-on system that allows for gene manipulation in osteoprogenitors specifically in postnatal mice. Therefore, we propose to delete ¿-catenin in osteoprogenitors postnatally to test the hypothesis that ¿-catenin directly regulates bone formation in postnatal life (Aim 1). A second critical barrier to progress in the field is the lack of understanding of the molecular mechanisms that mediate Wnt function in osteoblast-lineage cells. Research has been hindered by the lack of a robust mouse model in which a Wnt protein can be manipulated and assessed for its acute signaling ability in vivo. We have now developed such a model wherein a potent bone anabolic Wnt ligand can be activated in a controlled manner. Therefore, in Aims 2 and 3, we will employ this new mouse model to investigate both biochemically and genetically the signal transduction mechanisms through which Wnt7b induces bone formation in vivo. PUBLIC HEALTH RELEVANCE: Novel strategies are required to safely promote bone formation to treat osteoporosis. Wnt signaling has been known to stimulate bone formation and provides a promising target pathway for developing novel bone anabolic agents, but the underlying molecular mechanisms are not well understood. This proposal is designed to understand the mechanism responsible for the potent bone-stimulating function of Wnt proteins. Research results from this study will provide a molecular framework for developing novel bone-enhancing pharmaceutics.

描述（由申请人提供）：Wnt 信号传导为开发新型骨合成代谢剂提供了有希望的靶途径，迄今为止大多数研究都支持成骨细胞谱系细胞中的自分泌或旁分泌 Wnt 信号传导直接控制成骨细胞生物学的模型。最近的一项研究提出了挑战，该研究得出的结论是，Wnt 蛋白的辅助受体 LRP5 并不直接在成骨细胞中发挥作用，而是通过调节肠道内血清素的产生来发挥作用。因此，研究对骨中直接 Wnt 信号传导的生理相关性产生了不确定性，造成这种不确定性的主要原因是 ¿ 的基因缺失。 2.3Col1-Cre 在成骨细胞中的连环蛋白（典型 Wnt 信号传导的必需效应子）不会影响出生后动物的成骨细胞数量或功能。之前在小鼠胚胎中的研究表明 Wnt/Lrp5/¿ -catenin 信号传导可能在 2.3Col1-Cre 激活之前的阶段发挥作用，由于缺乏适当的遗传工具，在出生后直接测试这一概念并不可行。因此，我们建议删除 ¿ -出生后骨祖细胞中的连环蛋白，以检验 ¿ -连环蛋白直接调节出生后的骨形成（目标 1）。该领域进展的第二个关键障碍是缺乏对介导成骨细胞谱系细胞 Wnt 功能的分子机制的了解。我们现在开发了一种强大的小鼠模型，可以在其中操纵和评估 Wnt 蛋白的体内急性信号传导能力，从而可以以受控方式激活有效的骨合成代谢 Wnt 配体。如图 2 和 3 所示，我们将利用这种新的小鼠模型从生化和遗传学方面研究 Wnt7b 在体内诱导骨形成的信号转导机制。公共健康相关性：需要新的策略来安全地促进骨形成来治疗骨质疏松症，已知 Wnt 信号传导可以刺激骨形成，并为开发新型骨合成代谢药物提供有希望的靶途径，但其潜在的分子机制尚不清楚。该提案旨在了解 Wnt 蛋白强效骨刺激功能的机制，该研究结果将为开发新型骨增强药物提供分子框架。