MECHANISMS OF ACTION OF HUMAN BONE RESORPTIVE CYTOKINES

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The objective of the proposed research is to elucidate the molecular mechanisms involved in the action of bone resorptive cytokines including interleukin 1 alpha, interleukin 1 beta, tumor necrosis factor, lymphotoxin, transforming growth factor alpha and transforming growth factor beta. The proposed research will characterize the effect of these cytokines on second messenger pathways in three bone systems: intact fetal rat long bone in organ culture, isolated osteoblasts and isolated osteoclasts. The interaction of interleukin 1 with agents that elevate cyclic AMP will be examined in whole bone. The effect of resoprtive cytokines on the cyclic AMP pathway in isolated osteoblasts will be determined by measuring cAMP by radioimmunoassay. Effects on the phosphotidylinositol pathway will be determined by HPLC separation of radiolabeled inositol phosphates. The effect of resorptive cytoskines or calcium second messenger pathway will be examined by measuring cytosolic free calcium using the calcium sensitive flluorescent dye Fura-2. Isolated osteoclasts will be examined in the Boyde/Chambers system. The research will also examine pharmacologic agents known to modify second messenger pathways. The ultimate goal is to obtain an integrated model of the action of bone resorptive agents. Boine resorption is a prominent feature of certain chronic inflammatory diseases including periodontal disease, arthritis and osteomyelitis. Bone resorption, osteolytic lesions and hypdecalcemia also commonly occur in cancer. The proposed research is necessary to an understanding of the pathogenesis and treatment of bone diseases.