BMP-3 Signaling in the Formation and Regulation of Bone

骨形成和调节中的 BMP-3 信号传导

• 批准号: 7215643
• 负责人: Vicki Rosen
• 金额: $ 37.97万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215643
• 关键词: Accounting; Activins; Affect; Age; Animal Cap; Animals; BMP3 gene; Belief; Binding; Biological Assay; Biology; Bone Matrix; Bone Morphogenetic Proteins; Cell Line; Cell Maturation; Cells; Chinese Hamster Ovary Cell; Conditioned Culture Media; Connective Tissue; Embryo; Fracture Healing; Genotype; Goals; Growth; Growth and Development function; Implant; In Vitro; Individual; Knock-in Mouse; Knockout Mice; Ligaments; Ligands; Maintenance; Marrow; Mechanics; Mediating; Mus; Organ; Osteoblasts; Osteogenesis; Partner in relationship; Pathway interactions; Patients; Pattern; Periosteal Cell; Periosteum; Phenotype; Physiological; Play; Proteins; Range; Regulation; Reporter; Reporting; Research; Research Personnel; Role; Scanning; Signal Pathway; Signal Transduction; Skeletal Development; Skeletal system; Skeleton; Skin; Stimulus; Stromal Cells; Structure; Technology; Tendon structure; Therapeutic Agents; Tissues; Week; Xenopus; base; bone; bone morphogenetic protein 2; bone morphogenetic protein receptors; clavicle; clinically significant; gain of function; in vivo; inhibin; inhibitor/antagonist; interest; knockout animal; osteogenin; progenitor; programs; promoter; receptor; recombinase; substantia spongiosa

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.

描述（由申请人提供）：尽管在过去十年中对骨形态发生蛋白（BMP）的研究呈指数级增长，但我们实际上对单个BMP在骨骼中发挥的生理作用知之甚少。我们决定将这一建议集中在BMP 3在骨骼中的作用上，是基于几个重要的发现。首先，尽管BMP 3是骨中最丰富的BMP，占骨基质中储存的总BMP蛋白的65%，但对其生物学知之甚少。我们对BMP 3感兴趣的第二个原因是最近的报道，这些报道将体内BMP 3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相关联。最后，也许是最有趣的是我们的观察，BMP 3基因敲除小鼠显示出明确的骨表型，而骨骼模式没有变化。在5周龄时，BMP 3敲除动物的总骨小梁质量是其野生型同窝动物的两倍，表明BMP 3是骨质量的负调节剂。在体外，BMP 3能够在有效的成骨刺激物的存在下对成骨细胞分化发挥抑制作用。BMP 3用于负调节骨量的信号通路尚未确定。由于成骨BMPs现在是每年用于增加数千名患者骨形成的治疗剂，因此了解BMP 3如何对骨量发挥其调节作用具有广泛的临床意义。在本提案中，我们将：研究BMP 3信号传导的缺乏对骨骼的形成、生长和维持的影响（SA 1）;检查BMP 3表达增加对骨骼的形成、生长和维持的影响（SA 2）;剖析BMP 3信号传导通路（SA 3），并确定BMP 3在骨膜和骨领中调节骨形成的功能（SA 4）。我们相信，我们从实验计划中获得的信息将是理解单个BMP如何单独或相互结合在骨骼模式、骨形成和骨量维持中发挥作用的关键。