PHARMACOLOGICAL INFLUENCE OF ANTIRHEUMATIC DRUGS ON PROTEOGLYCANASES FROM INTERLEUKIN-1 TREATED ARTICULAR-CARTILAGE

The purpose of this study was to examine whether drugs used in the tre atment of arthritic disorders possess any inhibitory potential on the proteoglycanolytic activities of matrix metalloproteinases (MMPs), and to determine whether drugs which inhibit these enzymes also modulate the biosynthesis and release of proteoglycans (PGs) from interleukin-1 -(IL-1) treated articular cartilage explants. The cartilage-bone marro w extract and the glycosaminoglycan-peptide complex (DAK-16) dose-depe ndently inhibited MMP proteoglycanases in vitro when tested at concent rations ranging from 0.5 to 55 mg/mL, displaying an IC50 value of 31.7 8 mg/mL and 10.64 mg/mL (1.9 X 10(-4) M) respectively. 2-(hydroxyamino )-2-oxoethyl]-4-methyl-1-oxopentyl] -L-leucyl-L-phenylalaninamide (U-2 4522) proved to be a potent inhibitor of MMP proteoglycanases (IC50 va lue 1.8 X 10(-9) M). None of the other tested drugs, such as possible chondroprotective drugs, nonsteroidal anti inflammatory drugs (NSAIDs) , disease modifying antirheumatic drugs (DMARDs), glucocorticoids and angiotensin converting enzyme inhibitors tested at a concentration of 10(-4) M displayed any significant inhibition. Only U-24522, tested at a concentration ranging from 10(-4) to 10(-6) M, significantly inhibi ted the IL-1-induced augmentation of PG loss from cartilage explants i nto the nutrient media, whereas DAK-16 and the cartilage-bone marrow e xtract: were ineffective. DAK-16 and the cartilage-bone marrow extract did not modulate the IL-l mediated reduced biosynthesis and aggregabi lity of PGs by the cartilage explants. The addition of 10(-5) MU-24522 , however, partially maintained the aggregability of PGs ex vivo. In o ur experiments, both possible chondroprotective drugs as well as U-245 22 demonstrated no cytotoxic effects on chondrocytes. BIOCHEM PHARMACO L 53;11:1627-1635, 1997. (C) 1997 Elsevier Science Inc.