Novel Regulators of Bone Formation

描述（由申请人提供）：对出生后骨形成的调控知之甚少。我们最近发现了一种叫做Schnurri-3 （Shn3，也叫KRC）的接头蛋白，它控制着成人的骨量。Schnurri-3是一种与果蝇同源的哺乳动物，是成年骨形成的重要调控因子。缺乏Shn3的小鼠表现出骨硬化表型，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Runx2的蛋白水平，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之间复合物的形成。由于WWP1能够促进Runx2多泛素化和蛋白酶体依赖性降解，该复合物抑制Runx2功能。我们最近有证据表明，细胞因子TGF（）与Shn3/WWP1通路相交，并且该通路除Runx2外还有底物。因此，虽然我们的研究揭示了Shn3作为出生后骨量的调节因子的重要作用，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。

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.