ROLE OF ALPHA2BETA1 IN OSTEOBLAST FUNCTION AND DIFFERENTIATION

点击翻译按钮获取中文摘要

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.