BIOLOGY OF CELL-CELL COMMUNICATION IN BONE

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Skeletal remodeling is characterized by a series of "coupled" sequential interactions between osteoblastic and precursors and the differentiated bone forming osteoblast and bone resorbing osteoclast, which is controlled by a complex paracrine-endocrine-autocrine interplay between local and systemic osteotrophic factors. This multidisciplinary program will apply the techniques and concepts of cell and molecular biology to analyze cellular modes of biological responses to osteotrophic factors, and to pursue the role of cell-cell and cell matrix interaction in the transduction of these responses. Specific themes to be explored will be: 1) isolation and identification of factors produced by osteoblasts which induce the differentiation of precursor cells into resorptive osteoblasts which induce the differentiation of precursor cells into resorptive osteoclasts; 2) characterization of osteoclast-derived cytokines and other secretory products that modulate osteoblast differentiation; 3) examine signal transduction mechanisms which are essential for osteoclast regulation of osteogenesis; 4) examine the molecular control of bone resorption, emphasizing H+ ATPase amplification in differentiating cells of the pre-osteoclastic monocyte-macrophage lineage, protease(s) activation during osteoclast differentiation, and non-genomic signal transductive responses to 1,25(OH)2D3; and 5) analyze the expression and synthesis of cell matrix (integrins) and other cell adhesion molecules, as well as the relationship between regulation of osteoblast differentiation by osteotropic factors and their effect on cell communication via these integrins and cell adhesion molecules. A specialized resource center designated the "Cell Biology Core" will provide assistance in the development, preparation and maintenance of new cell lines and immunohistochemical techniques, and a centralized repository for cDNA probe.