Pharmacological influence of antirheumatic drugs on proteoglycans from interleukin-1 treated articular cartilage.
The purpose of this study was to examine whether drugs used in the treatment 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 marrow extract and the glycosaminoglycan-peptide complex (DAK-16) dose-dependently inhibited MMP proteoglycanases in vitro when tested at concentrations ranging from 0.5 to 55 mg/mL, displaying an IC50 value of 31.78 mg/mL and 10.64 mg/mL (1.9 x 10[-4] M) respectively. (R,S)-N-[2-[2-(hydroxyamino)-2-oxoethyl]-4-methyl-1-oxopentyl++  +]-L-leucyl-L-phenylalaninamide (U-24522) proved to be a potent inhibitor of MMP proteoglycanases (IC50 value 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 inhibited the IL-1-induced augmentation of PG loss from cartilage explants into the nutrient media, whereas DAK-16 and the cartilage-bone marrow extract were ineffective. DAK-16 and the cartilage-bone marrow extract did not modulate the IL-1-mediated reduced biosynthesis and aggregability of PGs by the cartilage explants. The addition of 10(-5) M U-24522, however, partially maintained the aggregability of PGs ex vivo. In our experiments, both possible chondroprotective drugs as well as U-24522 demonstrated no cytotoxic effects on chondrocytes.
Steinmeyer
J
J
Department of Pharmacology and Toxicology, Rheinische Friedrich-Wilhelms-Universitat Bonn, Germany.
Daufeldt
S
S
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001853:Bone Marrow / Q000737:chemistry; D002358:Cartilage, Articular / Q000187:drug effects* / Q000201:enzymology; D002417:Cattle; D004789:Enzyme Activation; D006025:Glycosaminoglycans / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D014020:Tissue Extracts / Q000494:pharmacology
D018501:Antirheumatic Agents; D006025:Glycosaminoglycans; D006877:Hydroxamic Acids; D007375:Interleukin-1; D009842:Oligopeptides; D010455:Peptides; D014020:Tissue Extracts; C079423:U 27391; C069161:DAK 16; C022474:proteoglycan-degrading metalloendopeptidases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases