Adult Bone Mass Regulation by Type 2 BMP Receptors

2 型 BMP 受体对成人骨量的调节

基本信息

批准号：
8850396
负责人：
Vicki Rosen
金额：
$ 51.89万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-19 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8850396
关键词：
ACVR2B gene Activin A type II receptor Activin Receptor Activins Adult Affect Aging Animals Area Attention BMPR2 gene Binding Biological Assay Biological Availability Bone Density Bone Diseases Bone Marrow Bone Matrix Bone Morphogenetic Proteins Bone Regeneration Cell Line Cell Lineage Cell Nucleus Cells Coculture Techniques Data Defect Disease Elderly Embryonic Development Engineering Event Family Fibrosis Fracture Future Glaucoma Goals Health Incidence Intervention Investigation Kidney Ligands Link Lung MADH2 gene Mediating Molecular Mus Normal Cell Osteoblasts Osteogenesis Osteoporosis Pathway interactions Personal Satisfaction Phenotype Physiological Play Population Primary Cell Cultures Production Regulation Risk Role Series Signal Pathway Signal Transduction Signaling Molecule Skeletal Development Skeletal bone Skeleton Testing Therapeutic Work bone bone cell bone loss bone mass bone morphogenetic protein receptors cell type in vivo insight member mouse model novel osteoprogenitor cell postnatal pulmonary arterial hypertension receptor repaired research study skeletal socioeconomics

项目摘要

DESCRIPTION (provided by applicant): Osteoporosis, a disease of low bone mineral density associated with increased risk of fracture, is both a significant health problem and a considerable socioeconomic burden and there remains an unmet need for new therapies that would reduce the incidence of osteoporosis in the US. Bone Morphogenetic Protein (BMP) signaling plays a prominent role in skeletal development and fracture repair, and there is increasing evidence positively linking BMP signaling to bone formation in the adult skeleton. Here, we focus on the cellular and molecular events that regulate BMP signaling in bone cells. We show, using a mouse model developed in our lab that changing the composition of the type 2 BMP receptor pool present on bone forming cells influences the amount of bone they produce in vivo. Surprisingly, when mice lack the type 2 BMP receptor, BMPR2, on bone forming cells, normal levels of BMP signaling in bone still occur, but there is an unexpected reduction in the level of Activin/TGFb signaling. In these mice, the cells that build bone work harder while the cells that destroy bone work at a normal pace, causing the animals to have high bone mass. We believe that our results are due to the fact that the remaining type 2 receptors present on bone forming cells, ACVR2A/B, are shared between BMPs and Activins, another group of signaling molecules that are known to negatively affect bone formation. BMPs and Activins now have to compete for the remaining type 2 receptors, and information suggests that this competition would favor BMPs. Collectively, this leads us to hypothesize that interplay between BMP and Activin/TGFb signaling regulates bone formation in the adult skeleton. In this proposal, we explore two interrelated ideas that impact how we view the interaction of BMP and Activin/TGFb signaling in the adult skeleton. First, we suggest that competition between BMPs and Activins for shared type 2 receptors is a physiological event that influences bone formation in vivo. Second, we suggest that signaling antagonism between the BMP and Activin/TGFb pathways occurring downstream of receptor engagement is another means by which the bone mass is regulated in the adult skeleton. In three specific aims, we ask: Why does removing BMPR2 from bone cells affect Activin signaling? What is the cellular mechanism leading to high bone mass in mice lacking BMPR2 expression in bones? And, does Activin signaling antagonize BMP signaling in the skeleton? These studies will add to our understanding of how bone formation is regulated by interactions between the BMP and Activin/TGFb pathways and could identify future therapeutic approaches to treat bone diseases.

描述（由申请人提供）：骨质疏松症是一种与骨折风险增加相关的骨矿物质密度低的疾病，既是一个重大的健康问题，也是一个相当大的社会经济负担，在美国，对降低骨质疏松症发病率的新疗法的需求仍然未得到满足。骨形态发生蛋白 (BMP) 信号在骨骼发育和骨折修复中发挥着重要作用，并且越来越多的证据表明 BMP 信号与成人骨骼中的骨形成存在正相关。在这里，我们重点关注调节骨细胞中 BMP 信号传导的细胞和分子事件。我们使用我们实验室开发的小鼠模型证明，改变骨形成细胞上存在的 2 型 BMP 受体池的组成会影响它们在体内产生的骨量。令人惊讶的是，当小鼠的骨形成细胞上缺乏 2 型 BMP 受体 BMPR2 时，骨中 BMP 信号传导的水平仍然正常，但 Activin/TGFb 信号传导的水平却出人意料地降低。在这些小鼠中，构建骨骼的细胞更加努力地工作，而破坏骨骼的细胞则以正常速度工作，导致动物具有高骨量。我们相信，我们的结果是由于骨形成细胞上存在的其余 2 型受体 ACVR2A/B 是 BMP 和激活素（另一组已知会对骨形成产生负面影响的信号分子）共享的。 BMP 和激活素现在必须竞争剩余的 2 型受体，并且信息表明这种竞争将有利于 BMP。总的来说，这使我们推测 BMP 和激活素/TGFb 信号之间的相互作用调节成人骨骼中的骨形成。在本提案中，我们探讨了两个相互关联的想法，这些想法影响我们如何看待成人骨骼中 BMP 和激活素/TGFb 信号传导的相互作用。首先，我们认为 BMP 和激活素之间对共享 2 型受体的竞争是影响体内骨形成的生理事件。其次，我们认为发生在受体结合下游的 BMP 和激活素/TGFb 途径之间的信号拮抗是成人骨骼中骨量调节的另一种方式。在三个具体目标中，我们要问：为什么从骨细胞中去除 BMPR2 会影响激活素信号传导？导致骨骼中缺乏 BMPR2 表达的小鼠出现高骨量的细胞机制是什么？而且，Activin 信号传导是否会拮抗骨骼中的 BMP 信号传导？这些研究将加深我们对 BMP 和 Activin/TGFb 通路之间的相互作用如何调节骨形成的理解，并可能确定未来治疗骨疾病的治疗方法。