Adult Bone Mass Regulation by Type 2 BMP Receptors

描述(由申请人提供)： 骨质疏松症是一种骨密度低的疾病，伴随着骨折风险的增加，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没有得到满足。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信号与成人骨骼中骨形成呈正相关。在这里，我们集中在骨细胞中调节BMP信号的细胞和分子事件。我们使用我们实验室开发的小鼠模型表明，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，当小鼠缺乏骨形成细胞上的2型BMP受体BMPR2时，骨中BMP信号的正常水平仍然存在，但激活素/TGFb信号水平意外下降。在这些小鼠中，形成骨骼的细胞工作得更努力，而破坏骨骼的细胞则以正常的速度工作，导致动物的骨量较高。我们认为，我们的结果是由于骨形成细胞上剩余的2型受体ACVR2A/B由BMP和激活素共享，激活素是另一组已知对骨形成产生负面影响的信号分子。BMPs和激活素现在必须竞争剩余的2型受体，有信息表明这场竞争将有利于BMPs。总而言之，这导致我们假设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。在这个提案中，我们探索了两个相互关联的想法，它们影响我们如何看待BMP和Activin/TGFb信号在成人骨骼中的相互作用。首先，我们认为BMPs和激活素对共享的2型受体的竞争是一个影响体内骨形成的生理事件。其次，我们认为，BMP和激活素/TGFb信号通路之间的信号拮抗发生在受体结合的下游，是成人骨骼中调节骨量的另一种方式。在三个具体目标中，我们问：为什么从骨细胞中移除BMPR2会影响激活素信号转导？在骨中缺乏BMPR2表达的小鼠，导致骨量增加的细胞机制是什么？而且，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是如何通过BMP和激活素/TGFb通路之间的相互作用进行调节的理解，并可能确定未来治疗骨骼疾病的方法。

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.