THE PROTEOGLYCAN METABOLISM, MORPHOLOGY AND VIABILITY OF ARTICULAR-CARTILAGE TREATED WITH A SYNTHETIC MATRIX METALLOPROTEINASE INHIBITOR

Matrix metalloproteinases (MMP) are among the key enzymes responsible for the proteolytic destruction of articular cartilage during chronic rheumatic diseases. Articular cartilage is one potential target for dr ugs designed to inhibit the activity of MMPs in order to stop or to sl ow down the proteolytic destruction of the extracellular matrix of car tilage. The purpose of this study was to investigate the effect of the synthetic inhibitor of MMPs U-24522 for its ability (1) to inhibit in vitro the activity of MMP-proteoglycanases; (2) to modulate the morph ology and viability of cartilage explants; and (3) to modify the biosy nthesis and release of proteoglycans from articular cartilage explants . U-24522 dose-dependently inhibited the activity of MMP-proteoglycana ses and significantly reduced the release of proteoglycans from interl eukin-1 treated bovine articular cartilage explants when tested at con centrations ranging from 10(-4) to 10(-9) M. This hydroxamic acid deri vative proved not to be harmful to chondrocyte viability and cartilage morphology. In addition, U-24522 had no effect on the rate of proteog lycan biosynthesis of interleukin-1 treated cartilage explants and inc reased the percentage of newly synthesized proteoglycans to form macro molecular aggregates. Thus U-24522 combines direct inhibitory potentia l on the activity of MMP-proteoglycanases with the inhibition of inter leukin-1 stimulated proteoglycan loss from articular cartilage explant s without affecting the morphology, viability and biosynthesis of prot eoglycans of bovine articular cartilage explants.