NITRIC-OXIDE AND PROTEOGLYCAN TURNOVER IN RABBIT ARTICULAR-CARTILAGE

Articular chondrocytes are known to synthesize large amounts of nitric oxide in response to exposure to interleukin-1,but the role of this r adical in proteoglycan turnover remains controversial. In this study, we used two different inhibitors of nitric oxide synthase, N-G-methyl- L-arginine and thiocitrulline. to stud,; the effects of nitric oxide o n the synthesis and breakdown of proteoglycan in rabbit articular cart ilage. Synthesis of nitric oxide by cartilage slices in response to tr eatment with interleukin-1 and a partially purified mixture of synovia l cytokines known as chondrocyte-activating factors peaked during the first 2 days of culture and then fell to low levels, despite daily rep lenishment with fresh medium and cytokines to the cultures. The produc tion of nitric oxide was completely inhibited by N-G-methyl-L-arginine and thiocitrulline, Interleukin-1 and the chondrocyte-activating fact ors inhibited proteoglycan synthesis and accelerated proteoglycan brea k-down in the slices of cartilage. Both nitric oxide synthase inhibito rs substantially counteracted the suppression of proteoglycan synthesi s but exacerbated proteoglycan catabolism occurring in response to int erleukin-1 and the chondrocyte-activating factors. The accelerated cat abolism was associated with increased levels of matrix metalloproteina ses in the conditioned medium. This dual effect of nitric oxide compli cates decision making with regard to the possible clinical application s of nitric oxide agonists or antagonists in diseases of cartilage.