Nitric Oxide(NO) is a toxic, inorganic, gaseous free redical produced during the metabolism of L-Arginine by NO synthase(NOS). It has been implicated in a rapidly growing number of physiological and pathophysiological processes such as cytotoxic effects against microbes and tumor cells, blood vessel dilation and neurotransmitter. NOS exists as several isoenzymes, the major distinction being between inducible forms(iNOS) and constitutive forms(cNOS). Cells which contain the latter enzymes rapidlly, but transiently, synthesize small amounts of NO. Cells expressing iNOS, in contrast, synthesize large amount of NO for an extended periods following a lag of several hours during which the enzymes are induced. Recently there is growing evidence implicating NO in immune regulation, inflammation, autoimmunity, and arthritis.
This study was performed to determine the role of NO in inflammatory arthritis, especially in rheumatoid arthritis(RA). NO production was measured indirectly as nitrite, a breakdown product of NO, ① in serum and synovial fluid from patients with RA and osteoarthritis(OA) and in serum of controls ② in the supernatant of cultured synovial tissue with RA and OA, And it was investigated whether human chondrocytes and synoviocytes can synthesize NO and if so, how the production is regulated by cytokines and antirheumatic drugs. The results are as follows ;
1. Serum nitrite concentrations in patients with RA and OA were higher than in controls. In both disease groups synovial fluid nitrite was higher than serum nitrite. Serum and synovial fluid concenrations in RA were higher than those in OA. However, those findings are not statistically significant.
2. Although these findings are not statistically significant, the concentration of nitrite in the supernatant of cultured synovial tissue with RA was higher than that in OA.
3. IL-1 β and TNF-α induced the biosynthesis of NO by chondrocytes and synoviocytes. While IGF-1 and TGF-β failed to provoke the production of NO. The biosynthesis of NO required an induction period of approximately 6 hours and was inhibited by L-NMMA and cycloheximide. Dexamethasone, indomethacin, gold sodium thiomalate and methotrexate had no effect on the induction of NO biosynthesis.
These results suggest that NO may perform some role as an inflammatory mediator in inflammatory arthritis. Manipulating the physiologic concentration of NO appears to be clinically useful approach to the treatment of inflammatory arthritis in future.
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