Complete understanding of the regulation of bone resorption by hormones and drugs could provide a rational basis for the treatment of metabolic bone diseases involving increased bone resorption (e.g. osteoporosis and Paget's disease) and of inflammatory bone lysis (e.g. periodontal disease and rheumatoid arthritis). Such information would also be useful for the problem of unpredictable bone graft resorption. New experimental models are needed to demonstrate the origin, differentiation, and regulation of bone resorbing cells. We have developed a model for osteoclastic bone resorption. The subcutaneous implantation of mineral-containing, devitalized bone particles (BP) in rats induces the appearance of multinucleated cells that have many features of in osso osteoclasts. These cells can be distinguished from foreign body giant cells elicited by particulate polymethylmethacrylate because only the former express tartrate-resistant acid phosphatase activity, calcitonin receptors, and ruffled borders overlying the bone substrate being resorbed. Using these models, we propose to investigate various aspects of the biology of the osteoclast: its differentiation, mechanisms of bone resorption, and regulation by bone-active agents.
The specific aims are to characterize the process of differentiation of osteoclasts induced by bone particles, to determine the role of mast cells and lymphocytes and the effect of non-steroidal anti-inflammatory agents in their differentiation and activity, and to elucidate the mechanism of PTH's effects on resorption. The methods to be used include histomorphometrics, electron microscopy, immunocytochemistry, cell culture, evaluation of calcitonin receptors, and biochemical assessment of tartrate-resistant acid phosphatase activity. By evaluating the sequence of differentiation of these osteoclasts and foreign body giant cells, we will test the hypothesis that they have separate progenitor cells. Furthermore, the mechanism of the effects of parathyroid hormone and of non-steroidal anti-inflammatory cells on differentiation and cellular activity will be determined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
7R01AR031330-05
Application #
3156036
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Project Start
1988-07-01
Project End
1992-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Bleiberg, I; Glowacki, J; Anklesaria, P et al. (1992) Origin of stromal cells associated with osteoclast recruitment in s.c. implants of bone particles in chimeric mice. Exp Hematol 20:957-61
Glowacki, J; Rey, C; Glimcher, M J et al. (1991) A role for osteocalcin in osteoclast differentiation. J Cell Biochem 45:292-302
DeFranco, D J; Glowacki, J; Cox, K A et al. (1991) Normal bone particles are preferentially resorbed in the presence of osteocalcin-deficient bone particles in vivo. Calcif Tissue Int 49:43-50