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BMP-3 Signaling in the Formation and Regulation of Bone

BMP-3 信号在骨形成和调节中的作用

基本信息

批准号：
7846421
负责人：
Vicki Rosen
金额：
$ 38.43万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-23 至 2010-09-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7846421
关键词：
Accounting Adult Affect Age Aging BMP2 gene BMP3 gene BMP4 BMP5 gene Biology Bone Matrix Bone Morphogenetic Proteins Cloning Development Distant Economic Burden Economics Elderly Embryo Enhancers Fracture Healing Genes Goals Healthcare Systems In Vitro Individual Knockout Mice LacZ Genes Mechanics Mesenchymal Stem Cells Musculoskeletal Diseases Nucleic Acid Regulatory Sequences Osteoblasts Osteogenesis Patients Pattern Periosteum Phenotype Physiological Production Quality of life Regulation Regulatory Element Reporter Reporting Research Resources Role Signal Transduction Site Skeleton Stimulus Therapeutic Agents Transgenic Organisms base bone bone mass clinically significant in vivo inhibitor/antagonist insight interest mineralization novel osteoblast differentiation osteogenic osteogenin public health relevance stem cell differentiation

项目摘要

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.

描述（由申请人提供）：该项目的长期目标是深入了解BMP 3调节骨生成的机制。尽管在过去的十年里，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在骨骼中的生理作用知之甚少。我们决定将这一建议集中在BMP 3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的报道，这些报道将体内BMP3水平的变化与骨折愈合、骨骼的机械负荷以及随着年龄的增长而发生的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敲除小鼠显示出高骨量表型，随着年龄的增长而增加。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。这些发现表明BMP 3是骨量的负调节剂。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BMP3如何对骨量产生负面影响具有广泛的临床意义。在这个建议中，我们专注于确定的顺式调节元件，目标BMP 3表达骨在体内，并确定是否可分离的软骨膜，骨膜和成骨细胞特异性增强子，调节BMP 3的表达，可以确定使用BMP 3 BAC克隆策略。公共卫生关系：肌肉骨骼疾病是医疗保健系统的主要经济负担，并对所有年龄段的人的生活质量和经济资源产生负面影响。该提案中概述的研究检查了BMP 3对骨形成和间充质干细胞分化产生负面影响的机制。更好地了解BMP 3对骨骼的影响将有助于开发新的肌肉骨骼疾病治疗方法。