The chronic inflammatory response which occurs during periodontal disease often results in tooth loss due to the destruction of alveolar bone. This destruction is likely, in part, to be the result of osteoclast stimulation by cytokines produced by the chronic inflammatory cells. In adult life, normal bone metabolism involves a balance between osteoclast- mediated resorption and osteoblast-mediated formation. this balance, referred to as coupling, results in no net change in overall bone throughout adult life. Most diseases relating to the skeletal system such as infectious (periodontal disease), metabolic (osteoarthritis, osteoporosis, renal osteodystrophy, Paget's), inherited (osteogenesis imperfecta, osteopetrosis), and tumor-based (osteosarcoma, giant cell tumor), involve abnormalities in the resorption-formation coupling. Bone resorption rates are determined by both the number and activity level of osteoclasts. A number of hormonal signals may influence osteoclast recruitment, differentiation, and/or activity either directly or indirectly. Clinically, glucocorticoid treatment for rheumatoid arthritis improves the health of periodontal tissue, but, paradoxically, treatment often results in glucocorticoid-induced osteoporosis. The mechanism by which glucocorticoids influence bone metabolism are not well understood. There are numerous reports of osteoblast responses to glucocorticoid treatments, but studies on glucocorticoid influences on bone resorption have shown opposing results. Evidence presented in this application suggests that highly purified osteoclasts contain glucocorticoid receptors and that glucocorticoids regulate osteoclast bone resorption. The objectives of the proposed studies are to verify the direct influence of glucocorticoids on osteoclast bone resorption and to identify some of the cellular effectors of this response. The specific aims of these studies are to: 1) identify and quantitate glucocorticoid receptors in avian osteoclasts and human giant cell tumors (osteoclastomas), 2) quantitate and characterize the effect of glucocorticoids on osteoclast resorption activity, 3) analyze the influence of glucocorticoids on osteoclast nuclear proto-oncogene expression and, 4) assess the influence of glucocorticoids on osteoclast nuclear proto-oncogene expression and, 4) assess the influence of glucocorticoids on gene expression of selected osteoclast proteins which have been implicated in the resorption process. Isolated avian osteoclasts and human osteoclastomas will be used to characterize osteoclast glucocorticoid receptors. In addition, avian osteoclast and human osteoclastoma cultures will be challenged with glucocorticoids to study the influence of glucocorticoids on bone resorption and gene responses in vitro.
|Effective start/end date||7/1/93 → 6/30/95|
- National Institute of Dental and Craniofacial Research
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