Novel Regulators of Bone Formation

骨形成的新型调节剂

• 批准号: 8099282
• 负责人: LAURIE Hollis GLIMCHER
• 金额: $ 8.73万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8099282
• 关键词: Adaptor Signaling Protein; Adult; Affect; Age; Aging; Albers-Schonberg disease; American; Biology; Bone Diseases; Bone Resorption; Cells; Complex; Coupled; Development; Diagnosis; Disease; Drosophila genus; Fracture; Genes; Hereditary Disease; Homologous Gene; Learning; Molecular; Mus; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Osteosclerosis; Pathogenesis; Pathway interactions; Phenotype; Polyubiquitination; Population; Prevention; Proteins; Regulation; Risk; Role; Signal Transduction; Skeleton; Tissues; abstracting; adapter protein; bone; bone mass; cytokine; improved; mature animal; multicatalytic endopeptidase complex; novel; osteoblast differentiation; postnatal; skeletal disorder; ubiquitin-protein ligase

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.

项目概要/摘要 我们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，也称为 KRC）的蛋白质，它控制哺乳动物的成年骨量。 果蝇 Shn 的同源物，是缺乏 Shn3 的成年小鼠骨形成的有效且重要的调节剂。 显示骨硬化表型，由于成骨细胞增强，骨量显着增加 Shn3 通过促进成骨细胞分化的主要调节因子 Runx2 的蛋白水平。 Shn3 的降解促进 Runx2 和 E3 泛素连接酶 WWP1 之间复合物的形成。 该复合物抑制 Runx2 功能，因为 WWP1 能够促进 Runx2 多泛素化和 我们最近有证据表明细胞因子 TGF¿与 相交 Shn3/WWP1 途径，并且该途径除了 Runx2 之外还有底物。 揭示了 Shn3 作为出生后骨量调节剂的重要作用，关于其功能和功能的许多问题 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作为骨形成的重要调节剂我们将 探究其在成骨细胞中的功能、上游诱导物、底物和下游靶标。 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的下游底物相关性 估计有 1000 万 50 岁以上的美国人患有骨质疏松症，其中 3400 万 美国人面临风险，加上美国人口老龄化，导致 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病的预防、诊断和治疗。 我们已经确定了一条由接头蛋白 Schnurri-3 和 控制成人骨形成的 E3 连接酶 WWP1 提供了令人兴奋的功能。 开发合成代谢物的目标，这些合成代谢物在成骨细胞水平上发挥作用，以增加 骨量。