Novel Regulators of Bone Formation

项目总结/摘要 对出生后骨形成的调控知之甚少。我们最近发现了一种适配器 一种名为Schnurri-3（Shn 3，也叫KRC）的蛋白质，控制成人骨量。Schnurri-3，一种哺乳动物 果蝇Shn的同源物，是成体骨形成的有效和必需的调节剂。缺乏Shn 3的小鼠 由于成骨细胞的增加，显示出骨量显著增加的成骨细胞表型 活动Shn 3通过促进成骨细胞分化的主要调节因子Runx 2的蛋白水平， 它的退化。Shn 3促进Runx 2和E3泛素连接酶WWP 1之间形成复合物。 该复合物由于WWP 1促进Runx 2多聚泛素化的能力而抑制Runx 2功能， 蛋白酶体依赖性降解。我们最近有证据表明，细胞因子TGF β与 Shn 3/WWP 1途径，并且该途径除了Runx 2之外还具有底物。因此，虽然我们的研究 揭示了Shn 3作为出生后骨量调节剂的重要作用，许多关于Shn 3功能和 Shn 3和WWP 1在成骨细胞生物学中作用机制仍然存在。 在这里，我们建议继续发现Shn 3作为骨形成的重要调节因子。 在成骨细胞中询问其功能、上游诱导物、底物和下游靶点。 我们有以下具体目标： 1)研究Shn 3和WWP 1在成骨细胞中的上游信号。 2)探讨Shn 3和WWP 1下游底物在成骨细胞中的相关性 骨质疏松症折磨着大约1000万50岁以上的美国人，其中3400万人患有骨质疏松症。 美国人处于危险之中，再加上美国人口老龄化， 预测到2020年，骨质疏松症相关骨折的发生率可能会增加两倍。 除非我们寻求改善骨骼疾病的预防、诊断和治疗。 我们已经确定了一个新的途径，包括一个衔接蛋白，Schnurri-3和 E3连接酶WWP 1控制成人骨形成。这些新的蛋白质提供了令人兴奋的 目标的发展，在成骨细胞的水平，以增加 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.