Effects of Antirheumatic Drugs on the Biosynthesis and Activation of Matrix Metalloproteinases and TIMP

Journal/Book: Z Rheumatol 1998; 57 Suppl. 1: 71 (P 106). 1998;

Abstract: Department of Pharmacology and Toxicology University of Bonn Objective: Production and activation of matrix metalloproteinases (MMP) are key events in the cartilage breakdown process during chronic inflammatory arthritides and osteoarthritis. The plasminogen activator (PA)-/plasmin system appears to be involved in the activation of collagenase (MMP-1) and stromelysin (MMP-3). Control over this enzymatic cascade is exerted by the specific inhibitors tissue inhibitor of metalloproteinases (TIMP) and plasminogen activator inhibitor (PAI). Interleukin-1 (IL-1) is known to modify the metabolic activities of chondrocytes. IL-1 is a potent inducer of proteolytic activities and inhibits the synthesis of PAI and TIMP. The aim of our study was to determine the potential of some antirheumatic drugs to reduce the IL-1 stimulated increase in proteolytic activities by either inhibiting the biosynthesis of the enzymes MMP-1 MMP-3 t-PA and u-PA and/or by stimulating the biosynthesis of the specific inhibitors TIMP-1 and PAI-1. Methods: Bovine chondrocytes were cultured in alginate beads for 8 days. For the final 48 hours cells were treated with 0 5 ng/ml IL-1 in the presence or absence of antirheumatic drugs. Expression of mRNA was analyzed bei RT-PCR with subsequent quantitation of products by PCR ELISA. Immunoprecipitation experiments were performed to evaluate TIMP and MMP-3 protein synthesis. PAI-1 protein was determined by ELISA. The activity of enzymes and inhibitors was also measured. The effects of drugs from different pharmacological groups were evaluated at a concentration of 10-5 M or lower. Results: IL-1 displayed differential effects on the proteins under study. This cytokine markedly stimulated the production of the proteases with a concomitant decreased synthesis of their inhibitors. The tested nonsteroidal antiinflammatory drugs tiaprofenic acid naproxen and indomethacin significantly reversed the IL-1 stimulatory effects on the biosynthesis of plasminogen activators. ... le

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