The effect of two non-steroidal antiinflammatory drugs (NASAIDs), indomethacin and its prodrug, indometacin farnesil (IMF), on the metabolism of proteoglycan and type II collagen was investigated using cultured human articular chondrocytes. Synthesis of these two matrix macromolecules was assessed by the incorporation of inorganic [35S]-sulfate into glycosaminoglycans and the production of type II procollagen carboxy-peptide (pCOL II-C) in culture. Indomethacin decreased chondrocyte type II collagen synthesis at 1 x 10-4 M which was a concentration greatly above its therapeutic dose; however, no suppression was observed with IMF concentrations of 1 x 10-6 to 10-4 M. No significant suppression of chondrocyte proteoglycan synthesis was shown with concentrations of indomethacin and IMF of 1 x 10-6 to 10-4 M. The effect of these two NSAIDs on matrix catabolism was evaluated by measuring matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinase-1 (TIMP-1) production using an enzyme immunoassay. Indomethacin inhibited interleukin-1β-induced MMP-3 production by chondrocytes only at 1 x 10-4 M, whereas moderate but significant inhibition was observed with concentrations of IMF of 1 x 10-6 M, which was its therapeutic dose. Stimulation of TIMP-1 production was observed with 1 x 10-5 M of indomethacin and 1 x 10-6 to 10-5 M of IMF. In the present experiment using IMF, it was likely that both IMF and a small amount of indomethacin derived from IMF affected chondrocyte metabolism. However, the above data suggests that IMF acts more favorably than indomethacin in chondrocyte culture in relation to matrix metabolism.
|Number of pages||12|
|Journal||Japanese Journal of Rheumatology|
|Publication status||Published - 01-12-1996|
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