NITRIC-OXIDE - A CYTOKINE-INDUCED REGULATOR OF BONE-RESORPTION

Nitric oxide (NO) has been reported to inhibit osteoclastic bone resor ption, yet potent stimulators of bone resorption, such as interleukin- 1 (IL-1) and tumor necrosis factor (TNF), are known to stimulate NO pr oduction, This paradox prompted us to reinvestigate the relationship b etween NO production and bone resorption in mouse calvarial organ cult ures, Control cultures and those stimulated with calciotropic hormones and individual cytokines produced little NO, and under these conditio ns the NO synthase inhibitor, L-N-G-monomethyl arginine (LMMA), had no significant effect on bone resorption. Cytokine combinations were muc h more potent stimulators of NO production than individual cytokines. Dramatic stimulation of NO production and inhibition of bone resorptio n resulted when gamma-interferon (IFN) was combined with IL-1 or TNF a nd these effects were reversed by LMMA. IFN had no effect on bone reso rption and little effect on NO production when used alone or in combin ation with calciotropic hormones, however, suggesting that IFN selecti vely inhibits cytokine-induced bone resorption by generating large amo unts of NO. IL-1 and TNF acted together to stimulate NO production but to a lesser degree than when combined with IFN, LMMA inhibited bone r esorption induced by IL-1 and TNF, suggesting that lower concentration s of NO stimulate bone resorption. Experiments with the pharmacologica l NO donor S-nitroso-acetyl-penicillamine (SNAP) supported this view i n showing generalized suppression of bone resorption at high SNAP conc entrations, but potentiation of IL-1 induced bone resorption at lower SNAP concentrations. We conclude that cytokines are potent inducers of NO in bone and that cytokine-induced NO production has biphasic effec ts on bone resorption. While the mechanisms of action of NO in bone wi ll require further research, these data raise the possibility that loc al production of NO may be involved in the regulation of bone remodeli ng, especially in diseases of cytokine activation such as rheumatoid a rthritis.