Requirement of the inducible nitric oxide synthase pathway for IL-1-induced osteoclastic bone resorption

Nitric oxide has been suggested to be involved in the regulation of bone tu rnover, especially in pathological conditions characterized by release of b one-resorbing cytokines, The cytokine IL-1 is thought to act as a mediator of periarticular bone loss and tissue damage in inflammatory diseases such as rheumatoid arthritis. IL-1 is a potent stimulator of both osteoclastic b one resorption and expression of inducible nitric oxide synthase (iNOS) in bone cells and other cell types. In this study, we investigated the role th at the iNOS pathway plays in mediating the bone-resorbing effects of IL-1 b y studying mice with targeted disruption of the iNOS gene. Studies in vitro and in vivo showed that iNOS-deficient mice exhibited profound defects of IL-1-induced osteoclastic bone resorption but responded normally to calciot ropic hormones such as 1,25 dihydroxyvitamin D3 and parathyroid hormone. Im munohistochemical studies and electrophoretic mobility shift assays perform ed on bone marrow cocultures from iNOS-deficient mice showed abnormalities in IL-1-induced nuclear translocation of the p65 component of NF kappa B an d in NF kappa B-DNA binding, which were reversed by treatment with the NO d onor S-nitroso-acetyl penicillamine. These results show that the iNOS pathw ay is essential for IL-1-induced bone resorption and suggest that the effec ts of NO may be mediated by modulating IL-1-induced nuclear activation of N F kappa B in osteoclast precursors.