Novel Regulators of Bone Formation

描述（由申请人提供）：对出生后骨形成的调节知之甚少。我们最近发现了一种名为Schnurri-3（Shn 3，也称为KRC）的衔接蛋白，它控制着成年人的骨量。Schnurri-3是果蝇Shn的哺乳动物同源物，是成年骨形成的有效和必需的调节剂。缺乏Shn 3的小鼠表现出成骨细胞表型，由于成骨细胞活性增强，骨量显著增加。Shn 3通过促进Runx 2的降解来控制Runx 2的蛋白水平，Runx 2是成骨细胞分化的主要调节因子。Shn 3促进Runx 2和E3泛素连接酶WWP 1之间形成复合物。该复合物抑制Runx 2功能，因为WWP 1能够促进Runx 2多聚泛素化和蛋白酶体依赖性降解。我们最近有证据表明，细胞因子TGF β 1与Shn 3/WWP 1途径交叉，并且该途径除了Runx 2外还有底物。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，但关于Shn 3和WWP 1在成骨细胞生物学中的作用和机制的许多问题仍然存在。 在这里，我们建议继续我们的发现，Shn 3作为一个重要的调节骨形成，我们将询问其功能，上游诱导剂，底物和下游目标的成骨细胞。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)研究Shn 3和WWP 1在成骨细胞中的下游底物 公共卫生相关性：骨质疏松症困扰着估计1000万50岁以上的美国人，其中3400万美国人处于风险中，并且加上美国人口的老龄化，导致预测到2020年骨质疏松症相关骨折的比率可能增加两倍，除非我们寻求改善骨骼疾病的预防、诊断和治疗。我们已经确定了一种新的途径，包括一个衔接蛋白，Schnurri-3和E3连接酶WWP 1控制成人骨形成。这些新的蛋白质为合成代谢物的发展提供了令人兴奋的目标，这些合成代谢物在成骨细胞的水平上起作用以增加骨量。

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.