The research described in this application is aimed at understanding of the molecular mechanisms by which bone resorption is regulated. Bone resorption is performed by the osteoclast and acidification of the extracellular bone resorbing compartment constitutes one of the major physiological constraint on the osteoclast. Agents that regulate the differentiation and/or function of the osteoclast affect, albeit not exclusively, the ion transporters and attachment molecules involved in the acidification process. Investigation f the mechanisms by which peptide and steroid hormones affect these processes will therefore help refine our understanding of their regulation. Furthermore, to try to elucidate the mechanisms in which the non-receptor tyrosine kinase c-src is involved and so critically needed for normal osteoclast function may open new avenues for therapeutic intervention. The overall aim of this proposal is to further characterize the specific isoforms of the ion transporters involved in osteoclast-mediated acidification and the mechanisms by which their expression and/or function in bone resorption are regulated. This will include examples of the three main regulatory pathways, i.e., steroid hormones, peptide hormones and the tyrosine kinase signal transduction pathway. This proposal will address the following specific aims: (1) Further analyze the mechanisms by which the peptide hormone calcitonin regulates the processes of acidification by kidney cells and osteoclasts and compare them to the action of PTHrP 107-111 and RGD-containing peptides; (2) Further elucidate the mechanisms by which c-src regulates the function of the osteoclast and, possibly, some of the processes involved in acidification. (3) Further analyze the role of the steroid hormones 1,25- dihydroxyvitamin D3 and estrogens in the regulation of the expression of the various genes required for acidification by the osteoclast; This research program is particularly relevant to health related issues since a detailed analysis of the molecular mechanisms of bone resorption and its regulation can provide more specific and, thereby, more efficient, means to regulate these processes in vivo, whether to therapeutically activate osteoclasts in diseases involving a reduced rate of bone resorption (osteopetrosis, growth deficiencies for instance) or to inactivate osteoclasts in diseases involving an increased bone resorption (osteoporosis, osteoarthritis, periodontal disease, Paget's disease, etc.).
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