Evidence for a pathogenic role of nitric oxide in inflammation-induced osteoporosis

Inflammatory disease is associated with increased production of nitric oxid e (NO) and activation of the inducible nitric oxide synthase (iNOS) pathway , Several studies have addressed the role of NO as a mediator of cytokine e ffects on bone cell activity in vitro. Stimulatory and inhibitory actions h ave been found, however, depending on the concentrations produced and model system used. In view of this, it has been difficult to predict whether inc reased production of NO during inflammation is likely to increase bone loss or prevent it, We have investigated the pathogenic role of NO in an animal model of inflammation-induced osteoporosis (IMO), NO production was increa sed in IMO when compared with controls (+344%; p < 0.01), and this was acco mpanied by activation of inducible NOS (iNOS) in the bone marrow space. Bon e mineral density (BMD) was reduced in IMO when compared with controls (-64 %; p < 0.01), and this was found to be associated with reduced osteoblast n umbers (-44%; p < 0.05) and increased osteoclast numbers (+38%; p < 0.01). The NOS inhibitor L-NMMA reversed the deleterious effects of IMO on bone ma ss and bone turnover, but L-NMMA had no effect on bone mass in control anim als. This study has important implications for many inflammatory diseases s uch as rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease which are associated with increased NO production and osteoporosis , Our data not only suggest that iNOS activation and increased NO productio n contribute to the pathogenesis of osteoporosis in these situations, but a lso suggest that NOS inhibitors could be of therapeutic value in the preven tion and treatment of such bone loss.