Novel Regulators of Bone Formation

项目摘要/摘要 对出生后骨形成的调节知之甚少。我们最近发现了一种适配器 一种名为SchNurri-3(Shn3，也叫KRC)的蛋白质，控制成年人的骨量。哺乳动物SchNurri-3 果蝇的同系物，是一种强有力的成人骨形成的重要调节因子。缺乏Shn3的小鼠 表现为骨硬化表型，骨量因成骨细胞增多而显著增加 活动。Shn3通过促进成骨细胞分化的主要调节因子Runx2的蛋白水平 它的退化。Shn3促进Runx2和E3泛素连接酶WWP1之间的复合体的形成。 该复合体由于WWP1促进Runx2多泛素化的能力而抑制了Runx2的功能 依赖蛋白酶体的降解。我们最近有证据表明，细胞因子转化生长因子β与 Shn3/WWP1途径，该途径除Runx2外还有底物。因此，在我们学习的同时， 揭示了Shn3作为出生后骨量调节器的重要作用，以及关于其功能和 Shn3和WWP1在成骨细胞生物学中的作用机制仍然存在。 在这里，我们建议继续发现Shn3作为骨形成的基本调节因子。我们将 询问其在成骨细胞中的功能、上游诱导物、底物和下游靶点。 我们有以下具体目标： 1)研究成骨细胞中Shn3和WWP1的上游信号。 2)研究Shn3和WWP1下游底物在成骨细胞中的相关性 据估计，50岁以上的美国人有1000万人患有骨质疏松症，其中3400万人 美国人处于危险之中，再加上美国人口老龄化，导致 预测到2020年，骨质疏松性骨折的发生率可能会增加两倍 除非我们寻求改善骨病的预防、诊断和治疗。 我们已经确定了一条新的途径，由一种适配蛋白SchNurri-3和一种 E3连接酶WWP1，控制成人骨形成。这些新的蛋白质提供了令人兴奋的 作用于成骨细胞水平的合成代谢产物的开发目标 骨量。

Project Summary / Abstract Little is known about the regulation of postnatal bone formation. We have recently identified an adaptor protein called Schnurri-3 (Shn3, also KRC) that controls adult bone mass. Schnurri-3, a mammalian homologue of Drosophila Shn, is a potent and essential regulator of adult bone formation. Mice lacking Shn3 display an osteosclerotic phenotype with profoundly increased bone mass due to augmented osteoblast activity. Shn3 controls protein levels of Runx2, the principal regulator of osteoblast differentiation, by promoting its degradation. Shn3 promotes the formation of a complex between Runx2 and the E3 ubiquitin ligase WWP1. This complex inhibits Runx2 function due to the ability of WWP1 to promote Runx2 polyubiquitination and proteasome-dependent degradation. We have recent evidence that the cytokine TGF¿ intersects with the Shn3/WWP1 pathway and that this pathway has substrates in addition to Runx2. Thus, while our studies reveal an essential role for Shn3 as a regulator of postnatal bone mass, many questions about the function and mechanism of action of Shn3 and WWP1 in osteoblast biology remain. Here we propose to pursue our discovery of Shn3 as an essential regulator of bone formation We will interrogate its function, upstream inducers, substrates and downstream targets in the osteoblast. We have the following specific aims: 1) Investigate the upstream signals of Shn3 and WWP1 in the osteoblast. 2) Investigate the downstream substrates of Shn3 and WWP1 in the osteoblast Relevance Osteoporosis afflicts an estimated 10 million Americans over age 50 with 34 million Americans at risk and coupled with the aging of the American population leads to the prediction that the rate of osteoporosis related fractures may triple by the year 2020 unless we seek to improve the prevention, diagnosis, and treatment of bone disease. We have identified a novel pathway consisting of an adapter protein, Schnurri-3 and an E3 ligase WWP1 that control adult bone formation. These new proteins offer exciting targets for the development of anabolics that act at the level of the osteoblast to increase bone mass.