EFFECTS OF INDOMETHACIN ON THE PRODUCTION OF MATRIX METALLOPROTEINASE-3 AND TISSUE INHIBITOR OF METALLOPROTEINASES-1 BY HUMAN ARTICULAR CHONDROCYTES

Objective. To study the action of indomethacin on cartilage catabolic activity by comparing the production of a matrix degrading proteinase and its inhibitor in human articular chondrocyte cultures. Methods. Ma trix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloprotei nases-1 (TIMP-1) in conditioned medium from human articular chondrocyt e cultures were measured using a onestep sandwich enzyme immunoassay. TIMP-1 mRNA expression was analyzed by Northern blotting using a 0.6 k b cDNA probe for human TIMP-1. Results. Human recombinant interleukin 1 beta (IL-1 beta) increased MMP-3 levels in primary chondrocyte cultu res. Indomethacin at 10(-5) M inhibited this IL-1 beta stimulation, bu t had no effect in the therapeutic range (10(-6)-10(-7) M). Low levels of indomethacin (10(-7) M) significantly increased the production of TIMP-1 by chondrocytes, Synthesis of TIMP-1 appeared to be inhibited b y prostaglandin E(2) (PGE(2)), since exogenously added PGE(2) reversed the stimulating effect of indomethacin on TIMP-1 production, Northern blot analysis showed that 10(-7) M indomethacin increased TIMP-1 mRNA levels in chondrocytes. Conclusion. Our findings indicate that low le vels of indomethacin can benefit matrix metabolism by affecting the ba lance of proteinases to their inhibitors in human articular cartilage.