BMP-3 Signaling in the Formation and Regulation of Bone

描述(申请人提供)：尽管骨形态发生蛋白(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在骨骼中扮演的生理角色知之甚少。我们决定将这项建议的重点放在BMP3在骨骼中的作用上是基于几个重要的发现。首先，尽管BMP3是骨中含量最丰富的BMP，占骨基质中储存的BMP总蛋白的65%，但人们对其生物学特性知之甚少。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年龄增长的内源性骨形成的丧失有关。最后，也许最耐人寻味的是我们观察到BMP3基因敲除小鼠表现出明确的骨表型，骨骼模式没有变化。在5周龄时，BMP3基因敲除动物的骨小梁总量是其野生型后代的两倍，这表明BMP3是骨量的负调节因子。在体外，BMP3能够在强大的成骨刺激下对成骨细胞的分化起抑制作用。BMP3负性调节骨量的信号通路尚未确定。由于成骨性BMP现在是每年在数千名患者中用于促进骨形成的治疗剂，了解BMP3是如何对骨量发挥调节作用的具有广泛的临床意义。在这个方案中，我们将：研究BMP3信号的缺失对骨骼的形成、生长和维持(SA1)的影响；检测BMP3表达增加对骨骼的形成、生长和维持的影响(SA2)；剖析BMP3信号通路(SA3)，并确定BMP3在骨膜和骨领中调节骨形成的功能(SA4)。我们相信，通过我们的实验计划获得的信息将是理解单个BMP如何单独以及彼此结合在骨骼构型、骨形成和骨量维持中发挥作用的关键。

DESCRIPTION (provided by applicant): Although research on the bone morphogenetic proteins (BMPs) has expanded exponentially over the past decade, we actually know very little about the physiological roles that individual BMPs play in the skeleton. Our decision to focus this proposal on role the BMP3 in bone is based on several important findings. First, although BMP3 is the most abundant BMP in bone, accounting for 65% of the total BMP protein 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 endogenous bone formation with age. Finally, and perhaps most intriguing is our observation that BMP3 knockout mice display an unequivocal bone phenotype without a change in skeletal patterning. At five weeks of age, the total trabecular bone mass of BMP3 knockout animals is twice that of their wild-type littermates, demonstrating that BMP3 is a negative regulator of bone mass. In vitro, BMP3 is able to exert an inhibitory effect on osteoblast differentiation in the presence of potent osteogenic stimuli. The signaling pathway used by BMP3 to negatively regulate bone mass has not yet been identified. As osteogenic BMPs are now therapeutic agents used to augment bone formation in thousands of patients each year, understanding how BMP3 exerts its regulatory effects on bone mass has wide ranging clinical significance. In this proposal, we will: investigate what the lack of BMP3 signaling does to the formation, growth and maintenance of the skeleton (SA1); examine the effects of increased BMP3 expression on the formation, growth and maintenance of the skeleton (SA2); dissect the BMP3 signaling pathway (SA3), and define the function of BMP3 in regulating bone formation in the periosteum and bone collar (SA4). It is our belief that the information we obtain as a result of our experimental plan will be key to understanding how individual BMPs, alone and in combination with one another, function in skeletal patterning, bone formation, and the maintenance of bone mass.