Novel Regulators of Bone Formation

骨形成的新型调节剂

• 批准号: 8573484
• 负责人: LAURIE Hollis GLIMCHER
• 金额: $ 21.58万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8573484
• 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; Health; 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; adapter protein; bone; bone mass; cytokine; improved; mature animal; multicatalytic endopeptidase complex; novel; osteoblast differentiation; postnatal; skeletal disorder; ubiquitin-protein ligase

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.

描述（由申请人提供）：对产后骨形成的调节知之甚少。我们最近确定了一种称为Schnurri-3（SHN3，也是KRC）的衔接蛋白，该蛋白控制成人骨骼。 Schnurri-3是果蝇SHN的哺乳动物同源物，是成人骨形成的有效且必不可少的调节剂。缺乏SHN3的小鼠表现出骨硬膜菌的表型，由于成骨细胞活性增强而导致骨骼质量大大增加。 SHN3通过促进其降解来控制Runx2的蛋白质水平，Runx2的主要调节剂是成骨细胞分化的主要调节剂。 SHN3促进了Runx2和E3泛素连接酶WWP1之间的复合物的形成。由于WWP1促进Runx2多泛素化和蛋白酶体依赖性降解，因此该复合物抑制了RUNX2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之外还具有底物。因此，尽管我们的研究揭示了SHN3作为产后骨骼质量的调节剂的重要作用，但许多有关SHN3和WWP1 In ot otology ot Ocology ot Octeolaster oplast oplast oplast oplast oplast oplast oplast oplast oplast oplast oplast blost blost botals质量的调节。 在这里，我们建议将SHN3作为骨形成的重要调节剂，我们将询问其功能，上游诱导剂，底物和成骨细胞中的下游靶标。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 公共卫生相关性：骨质疏松症遭受了估计的1000万美国人，年龄在50岁以上，有3400万美国人处于危险中，并且美国人口的老龄化会导致预测，除非我们寻求改善预防，诊断，诊断和治疗骨病，否则到2020年，与骨质疏松症相关骨折的发生率可能会达到三倍。我们已经确定了一种新的途径，该途径由适配蛋白，Schnurri-3和控制成人骨形成的E3连接酶WWP1组成。这些新的蛋白质为开发成骨细胞水平的合成代谢形成提供了令人兴奋的靶标，以增加骨骼质量。

项目成果

SMURF2 regulates bone homeostasis by disrupting SMAD3 interaction with vitamin D receptor in osteoblasts.

SMURF2 通过破坏 SMAD3 与成骨细胞中维生素 D 受体的相互作用来调节骨稳态。

• DOI: 10.1038/ncomms14570
• 发表时间: 2017-02-20
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Xu Z;Greenblatt MB;Yan G;Feng H;Sun J;Lotinun S;Brady N;Baron R;Glimcher LH;Zou W
• 通讯作者: Zou W

Cdh1 regulates osteoblast function through an APC/C-independent modulation of Smurf1.

• DOI: 10.1016/j.molcel.2011.09.024
• 发表时间: 2011-12-09
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Wan L;Zou W;Gao D;Inuzuka H;Fukushima H;Berg AH;Drapp R;Shaik S;Hu D;Lester C;Eguren M;Malumbres M;Glimcher LH;Wei W
• 通讯作者: Wei W

Administration of BMP2/7 in utero partially reverses Rubinstein-Taybi syndrome-like skeletal defects induced by Pdk1 or Cbp mutations in mice.

• DOI: 10.1172/jci59466
• 发表时间: 2012-01
• 期刊: The Journal of clinical investigation
• 作者: Jae-hyuck Shim;M. Greenblatt;Anju Singh;N. Brady;D. Hu;R. Drapp;W. Ogawa;M. Kasuga;T. Noda;Sang-Hwa Yang;Sang-Kyou Lee;V. I. Rebel;L. Glimcher

Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer.

• DOI: 10.1038/nature09387
• 发表时间: 2010-11-04
• 期刊: Nature
• 影响因子: 64.8

XBP1-Independent UPR Pathways Suppress C/EBP-β Mediated Chondrocyte Differentiation in ER-Stress Related Skeletal Disease.

• DOI: 10.1371/journal.pgen.1005505
• 发表时间: 2015-09
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Cameron TL;Bell KM;Gresshoff IL;Sampurno L;Mullan L;Ermann J;Glimcher LH;Boot-Handford RP;Bateman JF
• 通讯作者: Bateman JF