BMP-2 Regulation of Bone Homeostasis

描述（由申请人提供）：骨形态发生蛋白（BMPs）被认为是有效的骨形成剂，基于它们在成年动物中诱导新生骨形成的能力，BMP活性的这种独特特征导致BMPs被用作骨修复的治疗剂。内源性bmp在骨骼中的作用也引起了人们的强烈兴趣。在胚胎发育过程中去除单个成骨BMP （BMP 2、4、5、6、7）表明，任何单个BMP的损失都可以通过存在的其他BMP来补偿。去除成骨BMP组合的小鼠显示出多种骨骼表型，这与单个BMP在骨骼发育过程中协同工作以提供适当水平的BMP活性的观点一致。成人维持正常骨功能也需要BMP的活性，骨中BMP拮抗剂水平的增加会导致骨质减少、骨脆性和自发性骨折。我们最近的数据显示，肢体骨骼中BMP2的缺失会导致出生后小鼠普遍的自发性骨折（Tsuji等人，2006），确定BMP2是成人骨骼稳态的主要参与者。在这一建议中，我们假设BMP2是骨骼稳态所必需的，因为它在出生后肢体骨骼中具有独特的空间和时间表达模式，因此不能被其他bmp补偿。我们以三个具体目标来解决这一假设。在SA 1中，我们创建了一只小鼠，其中BMP2基因被视觉报告基因取代，提供了一种精确的方法来跟踪BMP2的表达。在SA 2中，我们研究了BMP2在维持成人骨骼中支持成骨细胞分化所需的骨髓基质细胞微环境中的作用。如果BMP2是维持骨髓基质微环境（允许成骨细胞分化）所必需的，那么BMP2的缺失将造成更严重的后果。在SA 3中，我们描述了wnt介导的成骨细胞分化对BMP2的需求。如果骨中最佳Wnt信号需要BMP2，则BMP2的丢失将造成更大的后果。实验计划的完成将使我们能够确定BMP2在骨稳态中的作用。

DESCRIPTION (provided by applicant): Bone morphogenetic proteins (BMPs) were identified as potent bone forming agents based on their ability to induce de novo bone formation in adult animals and this unique feature of BMP activity has led to use of BMPs as therapeutic agents in bone repair. It has also generated intense interest in defining the role endogenous BMPs play in the skeleton. Removal of individual osteogenic BMPs (BMPs 2, 4, 5, 6, 7) during embryonic development shows that loss of any individual BMP can be compensated for by the other BMPs present. Mice in which combinations of osteogenic BMPs have been removed display a variety of skeletal phenotypes, consistent with idea that individual BMPs work in concert during skeletal development to provide the appropriate levels of BMP activity. BMP activity is also required to maintain normal bone function in adults, and increasing the levels of BMP antagonists in bone leads to osteopenia, bone fragility and spontaneous fracture. Our recent data showing that loss of BMP2 from the limb skeleton leads to pervasive spontaneous fractures in the postnatal mice (Tsuji et al., 2006) identifies BMP2 as a primary participant in skeletal homeostasis in adults. In this proposal, we hypothesize that BMP2 is required for skeletal homeostasis because it has a unique spatial and temporal expression pattern in the postnatal limb skeleton and so cannot be compensated for by other BMPs. We address this hypothesis in three specific aims. In SA 1 we create a mouse in which the BMP2 gene is replaced by a visual reporter, providing a precise way to follow BMP2 expression. In SA 2 we investigate the role of BMP2 in maintaining the bone marrow stromal cell microenvironment that is required to support osteoblast differentiation in the adult skeleton. Loss of BMP2 would be of greater consequence if BMP2 were required for maintenance of the bone marrow stromal microenvironment that allows for osteoblast differentiation. In SA 3 we characterize the requirement for BMP2 in Wnt-mediated osteoblast differentiation. Loss of BMP2 would be of greater consequence if BMP2 were required for optimal Wnt signaling in bone. Completion of the experimental plan will allow us to define the role of BMP2 in bone homeostasis.