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有关的低骨矿物质密度疾病，既是重大的健康问题，又是一个相当大的社会经济负担，并且对新疗法的需求仍然未满足，这将减少美国骨质疏松症的发生率。骨形态发生蛋白（BMP）信号传导在骨骼发育和断裂修复中起着重要作用，并且有越来越多的证据将BMP信号与成人骨骼中的骨形成联系起来。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。我们显示，使用实验室中开发的小鼠模型，该模型改变了骨形成细胞上存在的2型BMP受体池的组成，从而影响了它们在体内产生的骨骼量。令人惊讶的是，当小鼠在骨形成细胞上缺乏2型BMP受体BMPR2时，仍会发生骨骼中BMP信号的正常水平，但是激活素/TGFB信号传导的水平出乎意料的降低。在这些小鼠中，建立骨骼的细胞更加努力地工作，而破坏骨骼的细胞则以正常的速度起作用，从而导致动物具有高骨头。我们认为，我们的结果是由于以下事实：骨形成细胞上存在的其余2型受体ACVR2A/B在BMP和激活素之间共享，BMP和激活素是另一组信号分子，这些信号分子已知会对骨形成产生负面影响。 BMP和激活素现在必须竞争其余2型受体，信息表明该竞赛将有利于BMP。总体而言，这使我们假设BMP与激活素/TGFB信号传导之间的相互作用调节成人骨骼中的骨形成。在此提案中，我们探讨了两个相互关联的想法，这些想法影响了我们如何看待成人骨骼中BMP和激活素/TGFB信号的相互作用。首先，我们建议BMP和激活素对共享类型2受体的竞争是影响体内骨形成的生理事件。其次，我们建议BMP和激活素/TGFB途径之间发生的信号拮抗作用是受体互动下游的途径，这是在成年骨架中调节骨骼质量的另一种手段。在三个特定目标中，我们问：为什么从骨细胞中去除BMPR2会影响激活素信号传导？什么是导致骨骼中缺乏BMPR2表达的小鼠高骨量的细胞机制？并且，激活素信号传导是否会拮抗骨骼中的BMP信号传导？这些研究将增加我们对BMP与激活素/TGFB途径之间相互作用如何调节骨骼形成的理解，并可以鉴定未来治疗骨骼疾病的治疗方法。