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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043225-06
Application #
6171348
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Sharrock, William J
Project Start
1994-12-01
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
6
Fiscal Year
2000
Total Cost
$224,312
Indirect Cost
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Larsen, Kirsten I; Falany, Marina; Wang, Wei et al. (2005) Glucose is a key metabolic regulator of osteoclasts; glucose stimulated increases in ATP/ADP ratio and calmodulin kinase II activity. Biochem Cell Biol 83:667-73
Wu, Xiaojun; Ahn, Eun-Young; McKenna, Margaret A et al. (2005) Fas binding to calmodulin regulates apoptosis in osteoclasts. J Biol Chem 280:29964-70
Wu, Xiaojun; Pan, George; McKenna, Margaret A et al. (2005) RANKL regulates Fas expression and Fas-mediated apoptosis in osteoclasts. J Bone Miner Res 20:107-16
Zayzafoon, Majd; Gathings, William E; McDonald, Jay M (2004) Modeled microgravity inhibits osteogenic differentiation of human mesenchymal stem cells and increases adipogenesis. Endocrinology 145:2421-32
Zhang, Liang; Feng, Xu; McDonald, Jay M (2003) The role of calmodulin in the regulation of osteoclastogenesis. Endocrinology 144:4536-43
Williams, J P; Thames 3rd, A M; McKenna, M A et al. (2003) Differential effects of calmodulin and protein kinase C antagonists on bone resorption and acid transport activity. Calcif Tissue Int 73:290-6
Sawyer, A; Lott, P; Titrud, J et al. (2003) Quantification of tartrate resistant acid phosphatase distribution in mouse tibiae using image analysis. Biotech Histochem 78:271-8
Wang, Qiang; Xie, Yi; Du, Quan-Sheng et al. (2003) Regulation of the formation of osteoclastic actin rings by proline-rich tyrosine kinase 2 interacting with gelsolin. J Cell Biol 160:565-75
Williams, John P; McKenna, Margaret A; Thames 3rd, Allyn M et al. (2003) Effects of cyclosporine on osteoclast activity: inhibition of calcineurin activity with minimal effects on bone resorption and acid transport activity. J Bone Miner Res 18:451-7
Wu, Xiaojun; McKenna, Margaret A; Feng, Xu et al. (2003) Osteoclast apoptosis: the role of Fas in vivo and in vitro. Endocrinology 144:5545-55

Showing the most recent 10 out of 21 publications