The proposed studies seek to define the molecular mechanisms by which the expression and function of gap junction proteins is controlled in bone cells. The cells involved in bone formation and remodeling must be able to function in concert to effectively maintain bone, and they do so in response to local and hormonal stimuli. One of the major ways in which cells communicate with each other is through gap junctions. Gap junctions are composed of hexamers of integral membrane proteins called connexins which form aqueous channels between the cytoplasm of adjacent cells. These structures allow electrical and chemical coupling of cells and are important in cell growth, oncogenesis, and development in many different cells. Gap junctions have been identified previously in bone cells by electron microscopy. Preliminary studies for this proposal have shown that human and rat osteoblastic cells and cell lines express three different members of the connexin family of gap junction proteins. Furthermore, osteoblastic cells differed in their ability to communicate through gap junctions, and the different connexins appear to play different roles in cell-cell communication in osteoblasts. Because many of the connexins have been cloned and sequenced, it is now possible to express individual gap junction proteins in cells that do not normally express them in order to study their function. The studies outlined in this proposal will define how the different gap junction proteins contribute to cell-cell communication in osteoblastic cells, and how the expression and function of these proteins are controlled by local and systemic mediators such as cytokines, hormones, and mediators of signal transduction that affect bone cell function. These studies may thereby elucidate important mechanisms by which bone cell function is regulated, and suggest novel ways in which bone remodeling can be influenced.
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