Novel Regulators of Bone Formation

描述(申请人提供)：对出生后骨形成的调节知之甚少。我们最近发现了一种称为SchNurri-3(Shn3，也叫KRC)的接头蛋白，它可以控制成人的骨量。SchNurri-3是果蝇Shn的哺乳动物同源物，是成人骨形成的有效和必要的调节因子。缺乏Shn3的小鼠表现为骨硬化型，由于成骨细胞活性增强，骨量显著增加。Shn3通过促进Runx2的降解来控制其蛋白质水平，Runx2是成骨细胞分化的主要调节因子。Shn3促进Runx2和E3泛素连接酶WWP1之间的复合体的形成。这种复合体由于WWP1能够促进Runx2的多泛素化和蛋白酶体依赖的降解而抑制Runx2的功能。我们最近有证据表明，细胞因子TGF()与Shn3/WWP1途径相交，并且该途径除了Runx2外还有底物。因此，虽然我们的研究揭示了Shn3作为出生后骨量调节的重要作用，但关于Shn3和WWP1在成骨细胞生物学中的功能和作用机制仍然存在许多问题。 在这里，我们打算继续我们的发现，Shn3作为骨形成的重要调节因子，我们将询问它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)研究成骨细胞中Shn3和WWP1的下游底物 公共卫生相关性：估计有1000万50岁以上的美国人患有骨质疏松症，3400万美国人处于危险之中，再加上美国人口的老龄化，预测到2020年，除非我们寻求改善骨病的预防、诊断和治疗，否则与骨质疏松症相关的骨折发生率可能会增加两倍。我们已经确定了一条新的途径，它由一个适配蛋白SchNurri-3和一个E3连接酶WWP1组成，它控制着成人的骨形成。这些新的蛋白质为合成代谢物质的开发提供了令人兴奋的靶点，这些合成代谢物质在成骨细胞水平上作用于增加骨量。

DESCRIPTION (provided by applicant): 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 PUBLIC HEALTH 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.