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 drugs designed to inhibit the activity of MMPs in order to stop or to slow down the proteolytic destruction of the extracellular matrix of cartilage. 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 morphology and viability of cartilage explants; and (3) to modify the biosynthesis and release of proteoglycans from articular cartilage explants. U-24522 dose-dependently inhibited the activity of MMP-proteoglycanases and significantly reduced the release of proteoglycans from interleukin-1 treated bovine articular cartilage explants when tested at concentrations ranging from 10(-4) to 10(-9) M. This hydroxamic acid derivative proved not to be harmful to chondrocyte viability and cartilage morphology. In addition, U-24522 had no effect on the rate of proteoglycan biosynthesis of interleukin-1 treated cartilage explants and increased the percentage of newly synthesized proteoglycans to form macromolecular aggregates. Thus U-24522 combines direct inhibitory potential on the activity of MMP-proteoglycanases with the inhibition of interleukin-1 stimulated proteoglycan loss from articular cartilage explants without affecting the morphology, viability and biosynthesis of proteoglycans of bovine articular cartilage explants.
Steinmeyer
J
J
Institut für Pharmakologie und Toxikologie, Rheinische Friedrich-Wilhelms-Universität Bonn, Germany.
Daufeldt
S
S
Kalbhen
D A
DA
D000818:Animals; D002358:Cartilage, Articular / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology*; D002417:Cattle; D004355:Drug Stability; D004789:Enzyme Activation / Q000187:drug effects; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D009924:Organ Culture Techniques; D011509:Proteoglycans / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*
D006877:Hydroxamic Acids; D009842:Oligopeptides; D011509:Proteoglycans; C079423:U 27391; C022474:proteoglycan-degrading metalloendopeptidases; D008666:Metalloendopeptidases