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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：
9260765
负责人：
Vicki Rosen
金额：
$ 52.22万
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/9260765
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 Osteoblasts Osteogenesis Osteoporosis Pathologic Pathway interactions Phenotype Physiological Play Population Primary Cell Cultures Production Regulation Role Series Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Skeletal Development Skeleton Testing Therapeutic Work bone bone cell bone loss bone mass bone morphogenetic protein 2 bone morphogenetic protein receptors cell type experimental study fracture risk in vivo insight member mouse model negative affect novel novel therapeutics osteoblast differentiation osteoprogenitor cell postnatal public health relevance pulmonary arterial hypertension receptor repaired 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低骨矿物质密度疾病，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起着重要作用，越来越多的证据表明BMP信号与成人骨骼中的骨形成正相关。在这里，我们专注于调节骨细胞中BMP信号的细胞和分子事件。我们表明，使用我们实验室开发的小鼠模型，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，当小鼠缺乏骨形成细胞上的2型BMP受体BMPR 2时，骨中的正常水平的BMP信号传导仍然发生，但激活素/TGF β信号传导的水平意外降低。在这些小鼠中，构建骨骼的细胞工作得更努力，而破坏骨骼的细胞以正常的速度工作，导致动物具有高骨量。我们认为，我们的结果是由于骨形成细胞上存在的剩余2型受体ACVR 2A/B在BMP和激活素之间共享，激活素是已知对骨形成产生负面影响的另一组信号分子。BMP和激活素现在必须竞争剩余的2型受体，信息表明这种竞争将有利于BMP。总的来说，这使我们假设BMP和激活素/TGF β信号传导之间的相互作用调节成人骨骼中的骨形成。在这个提议中，我们探讨了两个相互关联的想法，影响我们如何看待BMP和激活素/TGF β信号在成人骨骼中的相互作用。首先，我们认为骨形成蛋白和激活素之间对共享的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，BMP和激活素/TGF β通路之间的信号转导拮抗作用发生在受体接合的下游，是另一种手段，通过这种手段，在成人骨骼中的骨量进行调节。在三个具体的目标中，我们问：为什么从骨细胞中去除BMPR 2会影响激活素信号传导？在骨中缺乏BMPR 2表达的小鼠中导致高骨量的细胞机制是什么？激活素信号是否拮抗骨骼中的BMP信号？这些研究将增加我们对骨形成如何通过BMP和激活素/TGF β通路之间的相互作用进行调节的理解，并可以确定未来治疗骨病的治疗方法。