The long term objectives of this proposal are to characterize the cells, the interactions between the cells and with the bone matrix, and the regulation of the cellular events occurring during sequential bone remodeling. The specific aims of this renewal application are the following: l. Study the origin and fate of the osteoclast. 2. Characterize the mechanism of osteoclastic bone resorption and compare these functional characteristics to the activation and reversal phases and to the function of monocytes and macrophages. 3. Characterize the cells involved in the reversal phase and their relevance to the mechanism of coupling between resorption and formation. 4. Analyze the effects of hormones and drugs affecting the skeletal homeostasis and/or the bone remodeling activity on the various cells involved in the bone remodeling process and their functions. The main significance of this research program relates to its potential impact on the understanding of the pathogenesis of the numerous diseases of the skeleton involving a deregulation of the bone remodeling sequence, most frequently associated with an uncoupling or an imbalance beween the resorption and formation components of bone remodeling. Local bone loss such as that occurring in periodontal disease, rheumatoid arthritis or Paget's disease, or systemic imbalances such as that occurring in osteoporosis or osteopetrosis and high turnover diseases such as hyperparathyroidism are all ultimately related with dysfunctions of the sequence of events occurring during normal bone remodeling. The experimental approach selected in this project involves both in vivo and in vitro studies and a combination of histology, morphometry, enzyme histochemical studies, immunocytochemical studies, both at the light microscopic and electron microscopic levels. In addition, cell isolation and culture, cell fractionation, analysis of membrane proteins and characterization of surface antigens specific for various cell type or stages in their differentiation will be approached by the use of specific antibodies or their development when not available. In parallel, a number of studies will involve the analysis of the effects of hormones involved in the regulation of calcium and bone metabolism on bone cells, their differentiation and the homeostasis of the skeleton.