BMP Receptor Signaling and Bone Remodeling

描述(申请人提供)：问题：骨形成是一个动态的过程，受局部骨生长因子的调节。骨重建过程中的骨形成机制尚不清楚。骨形态发生蛋白(BMPs)是一种多功能的生长因子，调节多种生物学功能。BMP受体信号在成年小鼠骨形成和骨重建中的生理作用尚不完全清楚。 目的：探讨BMP受体信号转导在骨形成中的作用和机制。其基本假设是BMP受体信号在骨发育、出生后骨生长和成人骨改建过程中起着重要的骨形成作用。 方法：为探讨I型BMP受体在体内骨形成中的作用，我们建立了过表达显性-负性Ib型BMP受体(dnBMPR-IB)转基因小鼠。利用成骨细胞系特有的I型胶原启动子，将dnBMPRIB靶向成骨细胞。对这些转基因小鼠的骨骼表型的表征表明，BMP受体信号、骨生长和骨形成在1个月大的转基因小鼠中受到损害。这些转基因小鼠的骨密度、骨体积和骨形成率与1个月大的野生型小鼠相比显著降低。我们的结果表明，BMP受体信号是出生后体内骨形成所必需的组成部分。在拟议的研究中，我们计划使用相同的成年转基因小鼠进一步确定BMP受体在骨形成和骨重建中的作用。我们的工作假设是BMP受体信号在成年小鼠的骨形成和骨重建中起着关键作用。本研究的具体目的是利用Collal-dnBMPR-IB转基因小鼠模型来研究1)BMP受体1型在成年小鼠骨形成和骨重建中的作用，以及2)骨生长调节因子IGF-I和FGF-2或骨合成因子PTH是否通过激活BMP信号来诱导骨形成。 预期结果：拟议的研究将有助于更好地理解BMP信号在骨重建过程中骨形成中的生理重要性，并可能揭示骨质疏松症和其他相关疾病的病理后果。 益处：这些研究将提供对成年小鼠骨形成和骨重塑机制的分子洞察，并为治疗骨质疏松症和其他骨丢失相关疾病的药物开发确定分子靶点。

DESCRIPTION (provided by applicant): Problem: Bone formation is a dynamic process and is regulated by local bone growth factors. The mechanisms of bone formation during bone remodeling remain undefined. Bone morphogenetic proteins (BMPs) are multi-functional growth factors, which regulate a variety of biological functions. The physiological role of BMP receptor signaling in bone formation and bone remodeling in adult mice is not fully understood. Purpose: We will determine the role and mechanism of BMP receptor signaling in bone formation. The underlying hypothesis is that BMP receptor signaling plays an essential role in bone formation during bone development, postnatal bone growth and adult bone remodeling. Methods: To investigate the role of the type I BMP receptors in bone formation in vivo, we have generated transgenic mice, which overexpress a dominant-negative type IB BMP receptor (dnBMPR-IB) transgene. Expression of dnBMPRIB was targeted to ostcoblasts by using a type I collagen promoter, which is specific for the osteoblast lineage. Characterization of the skeletal phenotype of these transgenic mice has shown that BMP receptor signaling, bone growth and bone formation are impaired in 1-month-old transgenic mice. Bone mineral density, bone volume and bone formation rates in these transgenic mice are significantly reduced compared with 1-month-old wild-type littermates. Our results show that BMP receptor signaling is a necessary component for postnatal bone formation in vivo. In the proposed studies, we plan to further determine the role of BMP receptor in bone formation and bone remodeling using the same adult transgenic mice. Our working hypothesis is that BMP receptor signaling plays a critical role m bone formation and bone remodeling in adult mice. The specific aims are that we will use the Collal-dnBMPR-IB transgenic mouse model to determine 1) the role of the type 1 BMP receptor in bone formation and bone remodeling in adult mice and 2) whether the bone regulatory growth thctors IGF-I and FGF-2 or the bone anabolic agent PTH induce bone formation through activating BMP signaling. Expected Outcomes: The proposed studies will lead to a better understanding of the physiological importance of BMP signaling in bone formation during bone remodeling and likely uncover the pathological consequences for osteoporosis and other related diseases. Benefit: These studies will provide molecular insights into the mechanism involved in bone formation and bone remodeling in adult mice and define molecular targets for drug development for the treatment of osteoporosis and other bone-loss associated diseases.