The osteoclast, whose activity depends upon its ability to polarize, is the principal, if not exclusive, resorptive cell of bone, and thus responsible for the alveolar loss of periodontal disease. Mice, in whom the c-src gene has been deleted, generate osteoclasts incapable of bone resorption due to failure to develop a polarized ruffled membrane. The dysfunctional nature of c-src -/- osteoclasts eventuates in osteopetrosis, a mutation rescued by marrow transplantation. Thus, the product of the c-src gene, pp60c-src, is a protein essential to normal osteoclast function and its regulation may provide opportunities to modulate the resorptive process. Generation of mammalian osteoclasts from their marrow precursors requires accessory cells in the form of osteoblasts or marrow stromal cells. The Principal Investigator has found that as macrophages co-cultured with the stromal line, ST2 in the presence of 1, 25 [OH]2D3 (D3) and dexamethasone (Dex), differentiate into osteoclasts, they progressively express c-src both at the protein and mRNA levels. Most importantly, c-src-inducing activity is present in medium conditioned by ST2 cells. Furthermore, this investigator has found that cytokines known to be secreted by stromal cells fail to enhance macrophage c-src which is also not induced by arachidonate metabolites or bone-seeking steroids. These data suggest, but do not prove, the ST2-produced factor may be novel. On the basis of these observations it is hypothesized that the osteoclastogenic stromal line ST2, secretes, under the influence of D3 and Dex, a factor which induces c-src expression by osteoclast precursors as they differentiate. Thus, the specific aims are to: 1. Characterize the ST2 stromal cell-secreted, c-src inductive factor; 2. Determine the mechanisms by which D3 and Dex regulate expression of the ST2 stromal cell-secreted c-src inductive factor; 3. Determine the mechanism by which the ST2 stromal cell-secreted factor induces c-src in osteoclast precursors.