INTEGRIN/ECM INTERACTIONS IN BONE FORMATION AND REMODELING

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Cell interactions with extracellular matrix and with neighboring cells (the solid state environment) are critical for tissue morphogenesis during development, and for tissue homeostasis and remodeling throughout life. Previous studies from these laboratories using osteoblastic cells in cultured, have shown that integrin interactions with fibronectin play critical roles in both osteoblast differentiation and survival. The overall goal of the proposed studies is to test the physiologic relevance of these observations using transgenic mouse models. In one such model a truncated form of the integrin beta 1 subunit has been expressed in mature osteoblasts of transgenic mice. Preliminary characterization on the phenotype has revealed defective bone matrix deposition by osteoblasts and excessive bone remodeling by osteoblasts in post-natal young animals. In Aim 1, this phenotype will be characterized further at the bone tissue level by analysis of tissue architecture and matrix and mineral quality, using histomorphometry, and advanced imaging technologies in collaboration with project 6. The phenotype will also be characterized at the cellular level by determining the effects of transgene expression on the adhesion migration and survival of osteoblasts isolated from wildtype and transgenic mice. Finally, effects of this transgene on the biomechanical properties and repair capabilities will be studied in collaboration with Project 2. Studies in Aim 2 will focus on the role of fibronectin in osteoblast differentiation and survival in vivo. The N-terminal 70 kDa matrix assembly and collagen binding domain will be expressed in osteoblasts of transgenic mice. This domain was shown previously to suppress the differentiation of cultured immature primary osteoblasts and to trigger apoptosis of mature cultured osteoblasts. The phenotype will be characterized using the approaches and interactions indicated for Aim 1. In addition, the ability of intact fibronectin or fragments of fibronectin to accelerate or interfere with skeletal repair will be tested in a distraction osteogenesis model in collaboration with Project 2. Since there are currently no animal models that test the roles of fibronectin and its integrin receptors in osteoblast function and bone remodeling, these studies should provide novel insights with relevance to skeletal repair and skeletal degenerative disorders.