Bone loss secondary to increased bone resorption is a major contributor to the development of osteoporosis. Management of these conditions is hindered by poor understanding of the basic cellular biology of bone metabolism. This research program is focused upon elucidating the cellular and molecular control mechanisms which regulate osteoclast activity so that new pharmacotherapeutic agents may be developed that specifically target this bone resorbing cell. In the first funding period, we determined that tamoxifen inhibits mature osteoclast activity by disrupting Ca/2+/calmodulin and protein kinase C signaling cascades by a mechanism that is independent of estrogen. We have begun elucidating the specific intracellular molecular targets of these effects. The program will continue to use tamoxifen to characterize the rate limiting molecular steps in osteoclast metabolism using chicken, rabbit and human osteoclasts.
The specific aims are: I. Determine the mechanisms by which tamoxifen-induced alterations in intracellular calcium and calmodulin signaling inhibit bone resorption. Part A. Purify and characterize the specific 76 kDA tamoxifen binding protein in osteoclasts. Part B. Characterize the effect of tamoxifen treatment on calmodulin dependent signaling. Part C. Characterize the effect of tamoxifen treatment on calmodulin dependent signaling. Part C. Characterize tamoxifen-induced [Ca/2+}/i transients by bone attached osteoclasts. II. Determine the role of protein kinase Calpha in tamoxifen signaling intact osteoclasts. Part B. Determine the role of protein kinase Calpha in tamoxifen dependent inhibition of H+-pumping activity in isolated ruffled membranes. In addition to the approximately $14 billion per year spent on osteoporotic fractures, according to Healthy People 2000, 28% of all cancers in women are of breast origin, and are commonly associated with increased bone resorption and hypercalcemia. Cancer deaths in general are more prevalent in blacks than whites and postmenopausal osteoporosis in women is the major cause of approximately 1.3 million bone fractures each year. Together the morbidity and mortality due to increase rates of bone resorption in elderly and cancer patients represents a huge cost in health care dollars. Future osteoclast-targeted pharmacotherapeutics, the ultimate goal of this program, would benefit this broad population including minorities and women.
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