BMP-3 Signaling in the Formation and Regulation of Bone

描述（由申请人提供）：该项目的长期目标是深入了解BMP3调节成骨的机制。尽管对骨形态发生蛋白（BMPs）的研究在过去十年中呈指数级增长，但我们实际上对单个BMPs在骨骼中的生理作用知之甚少。我们决定把这个建议的重点放在BMP3上是基于几个重要的发现。首先，尽管BMP3是骨中最丰富的BMP，占骨基质中储存的BMP总量的65%以上，但对其生物学知之甚少。我们对BMP3感兴趣的第二个原因是，最近有报道称体内BMP3水平的变化与骨折愈合、骨骼的机械负荷以及随着年龄增长而发生的骨形成丢失有关。最后，也许是最有趣的是，我们观察到BMP3缺失小鼠显示出高骨量表型，随着年龄的增长而增加。在体外，BMP3能够在强效成骨刺激下对成骨细胞分化发挥抑制作用。这些发现表明BMP3是骨量的负调节因子。由于成骨bmp现在是每年成千上万患者用于增加骨形成的治疗剂，了解BMP3如何对骨量产生负面影响具有广泛的临床意义。在本研究中，我们着重于鉴定体内靶向BMP3骨表达的顺式调控元件，并确定是否可以使用BMP3 BAC克隆策略鉴定可分离的软骨外膜、骨膜和成骨细胞特异性增强子来调控BMP3表达。

DESCRIPTION (provided by applicant): The long-term goals of this project are to gain insights into the mechanisms by which BMP3 regulates osteogenesis. Although research on bone morphogenetic proteins (BMPs) has expanded exponentially over the past decade, we actually know very little about the physiological roles that individual BMPs have in the skeleton. Our decision to focus this proposal on BMP3 is based on several important findings. First, although BMP3 is the most abundant BMP in bone, accounting for over 65% of the total BMP stored in bone matrix, little is known about its biology. A second reason for our interest in BMP3 are recent reports that correlate changes in BMP3 levels in vivo with fracture healing, mechanical loading of the skeleton, and the loss of bone formation that occurs with aging. Finally, and perhaps most intriguing, is our observation that BMP3 null mice display a high bone mass phenotype that increases with advancing age. In vitro, BMP3 is able to exert an inhibitor effect on osteoblast differentiation in the presence of potent osteogenic stimuli. These findings suggest that BMP3 is a negative regulator of bone mass. As osteogenic BMPs are now therapeutic agents used to augment bone formation in thousands of patients each year, understanding how BMP3 exerts its negative effect on bone mass has wide-ranging clinical significance. In this proposal, we focus on identifying the cis-regulatory elements that target BMP3 expression to bone in vivo, and determining if separable perichondrial, periosteal and osteoblast-specific enhancers that regulate BMP3 expression can be identified using a BMP3 BAC cloning strategy. PUBLIC HEALTH RELEVANCE: Musculoskeletal diseases present a major economic burden to the healthcare system, and negatively affect the quality of life of people of all ages and economic resources. Research outlined in this proposal examines the mechanism by which BMP3 exerts a negative effect on bone formation and on mesenchymal stem cell differentiation. A better understanding of the influences of BMP3 on the skeleton will allow for the development of novel treatments for musculoskeletal disorders.