ADENYL-CYCLASE AND INTERLEUKIN-6 ARE DOWNSTREAM EFFECTORS OF PARATHYROID-HORMONE RESULTING IN STIMULATION OF BONE-RESORPTION

Parathyroid hormone and other bone resorptive agents function, at leas t in part, by inducing osteoblasts to secrete cytokines that stimulate both differentiation and resorptive activity of osteoclasts. We previ ously identified two potentially important cytokines by demonstrating that parathyroid hormone induces expression by osteoblasts of IL-6 and leukemia inhibitory factor without affecting levels of 14 other cytok ines, Although parathyroid hormone activates multiple signal transduct ion pathways, induction of IL-6 and leukemia inhibitory factor is depe ndent on activation of adenyl cyclase, This study demonstrates that ad enyl cyclase is also required for stimulation of osteoclast activity i n cultures containing osteoclasts from rat long bones and UMR106-01 ra t osteoblast-like osteosarcoma cells. Since the stimulation by parathy roid hormone of both cytokine production and bone resorption depends o n the same signal transduction pathway, we hypothesized that IL-6 migh t be a downstream effector of parathyroid hormone, We found that addit ion of exogenous IL-6 mimics the ability of parathyroid hormone to sti mulate bone resorption. More inportantly, an antibody directed against the IL-6 receptor blocks moderate stimulation of osteoclast activity induced by the hormone. Interestingly, strong stimulation of resorptio n overcomes this dependence on IL-6. Thus, parathyroid hormone likely induces multiple, redundant cytokines that can overcome the IL-6 requi rement associated with moderate stimulation. Taken together with studi es showing that many other bone resorptive agents also stimulate IL-6 production, our results suggest that IL-6 may be a downstream effector of these agents as well as of parathyroid hormone.