This proposal is designed to investigate how osteoclasts arise and are modulated. Knowledge of the cellular ontogeny and biology of the osteoclast, presently incomplete, is essential if we are to understand and treat such disorders as osteoporosis, metabolic bone disease, rheumatoid arthritis, osteopetrosis, and periodontitis, all of which involve disturbances in the balance between bone formation and resorption. Additionally, therapies such as orthodontic tooth movement, used to treat congenital craniofacial deformities and malocclusion, have as their basis cellular interactions which are poorly understood at present. A better understanding of these interactions would ultimately result in more effective, rational therapy in both of these general areas. The ontogeny of the osteoclast will be examined by creating monoclonal antibodies to so-called differentiation antigens expressed on the surface of osteoclast-like cells grown in culture from monocytes. The use of a fluorescence activated cell sorter (FACS) will allow a determination of how the mean antigen density per osteoclast-like cell compares with that of other cells coming from the culture which gave rise to the putative osteoclasts and from live animals. Thus, a picture of the putative osteoclast's antigenic identity will appear. The ability of the osteoclast-like cell to respond to various substances, active in bony remodeling, such as calcitonin and di(OH)2 vitamin D, will also be determined using assessments of the effects of these substances on the differentiation and function of these cells. Effects which these substances have on surface antigen expression will be examined using the monoclonal antibodies produced, and parameters such as yield of the culture system (for 1,25(OH)2 vitamin D) and cellular cyclic AMP levels (for calcitonin) will be used to determine how these substances affect the osteoclast-like cells functionally. Thus, a better understanding of the ontogeny and modulation of the osteoclast will result from this project.
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