ROLE OF ALPHA2BETA1 IN OSTEOBLAST FUNCTION AND DIFFERENTIATION

骨是高度动态的组织，主要由细胞和骨基质组成。 大量的细胞外基质发育过程中的骨形成， 组织重塑是由两个细胞介导的严格调节的过程， 专门的细胞类型，骨吸收破骨细胞和骨基质 分泌成骨细胞（OB），其中一些进一步发展成 骨细胞 骨骼在人的一生中会被广泛重塑， 骨形成与降解的不平衡导致病理性 如骨质疏松症，一种导致进行性 骨质流失 因此，细胞-基质相互作用的调节尤其重要。 对这个组织很重要。 骨ECM，大于85% 胶原蛋白L通过成骨细胞（OB）沉积和建模。 之甚少 了解OB-ECM相互作用如何协调骨形成， 它对外界刺激的反应（如机械力、系统性 激素），或者涉及哪些细胞表面受体。 整合素是 ECM受体的一个主要家族，也抑制来自 环境到细胞内部。 β 2 β 1是已知的 胶原蛋白L的整联蛋白受体，我们已经证明这种受体 在体外培养的成骨细胞和大鼠颅骨中的成骨细胞中表达。 α 2 β 1具有许多OB功能的潜在影响， 胶原沉积，基质重组， 矿化和对机械应变的响应。 通过 以下具体目标，我们建议测试的假设， α 2 β 1在OB发育的不同阶段具有不同的功能 α 2 β 1的功能和调节， OB功能和成熟过程中的决策点。 具体目标一。 确定α 2 β 1的亚细胞定位是否 原发性OB提示在不同时间点α 2 β 1功能的差异 分化阶段。 具体目标二。确定影响 将α 2的增强表达靶向至不同的OB群体 在原代培养物和转基因小鼠中。

Bone is highly dynamic tissue comprised primarily of cells and an extensive extracellular matrix. Bone formation during development and tissue remodeling is tightly regulated process mediated by two specialized cell types, bone resorbing osteoclasts and bone matrix secreting osteoblasts (OB), some of which further develop into osteocytes. Bones is extensively remodeled throughout life, and imbalance in bone formation vs. degradation leads to pathological conditions such as osteoporosis, a condition that leads to progressive bone loss. Thus, the regulation of cell-matrix interactions is especially important to this tissue. Bone ECM, which is greater that 85% collagen l, is deposited and modeled by osteoblasts (OB). Little is known about how OB-ECM interactions coordinate bone formation or its responses to external stimuli (e.g. mechanical forces, systemic hormones), or which cell surface receptors are involved. Integrins are a major family of ECM receptors, that also transduce signals from the environment to the cell interior. alph2beta1 is the major known integrin receptor for collagen l, and we have shown that this receptor is expressed by cultured OB in vitro and by OB in rat calvaria. alpha2beta1 has the potential influence many OB functions such as collagen deposition, matrix reorganization in preparation for mineralization, and response to mechanical strain. Through the following specific aims we propose to test the hypotheses that alpha2beta1 has distinct functions at different stages of OB development and that, alpha2beta1 function and regulation and critical at specific decision points during OB function and maturation. Specific Aim I. Determine whether the subcellular localization of alpha2beta1 in primary OB suggests differences in alpha2beta1 function at different stages of differentiation. Specific Aim II. Determine the effects of targeting enhanced expression of alpha2 to different populations of OB in primary cultures and in transgenic mice.