Skeletal remodeling is characterized by coordinated activities of osteoblasts and osteoclasts which are conditioned by matrix protein constituents, cell-cell interactions, and a variety of chemokine, cytokines, and growth factors. During the bone resorption process a variety of bone matrix constituents are released which serve to orchestrate bone remodeling via chemotaxis of osteoprogenitor cells to resorption sites and the stimulation, proliferation and differentiation of these cells into osteoblasts. Integrins have been implicated to play important roles in cell migration, target recognition, cell growth and differentiation in extraskeletal tissues. The role of cell surface integrins in either initiating and/or conditioning the coordinated osteoblastic component of the bone remodeling process, although ill- defined, is crucial since defective bone remodeling has been observed in transgenic animals with impaired integrin function in osteoblasts. The research proposed in this project is designed (i) to analyze the relationship of alphavbeta1, alphavbeta3 and alphavbeta5 integrins to osteoblast migration, adhesion, proliferation, and differentiation; (ii) to determine the signal transduction pathways which mediate the interaction between integrins and osteopontin, fibronectin, and type I collagen; and (iii) to study the effects of osteoblast inhibitory cytokines and chemokines (IL-8, TNF alpha and GRO) which are secreted by osteoclasts and specific osteogenic factors (bFGF, BMP-2, and TGF-beta) on the expression of integrins in osteoblasts and the roles of integrins in conditioning their effects on osteoblasts. The knowledge accumulated should clarify current concepts proposed to define mechanisms which control osteoblast development and activity, and also stimulate interest in developing new therapeutic modes for stimulating bone formation in disorders characterized by defective or deficient osteoblast activities. The acquired information should also further our knowledge with regard to the use of appropriate matrix proteins in orthopedic procedures where osteoblastic attachment is essential to guarantee normal bone formation and the integrity of either implanted bone tissue or porous non-osseous implants.
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