Investigation of the role of metalloproteinases in recombinant human interleukin-1 beta-induced degradation of rat femoral head cartilage.
The mechanism of proteoglycan (GAG) loss from rat femoral articular cartilage (FHC) induced by recombinant human interleukin-1 beta (rhIL-1 beta) in vitro has been investigated. The metalloproteinase inhibitor 1,10-phenanthroline, the serine proteinase inhibitor N alpha-p-tosyl-l-lysine chloromethyl ketone (TLCK), the activator of latent metalloproteinase p-aminophenylmercuric acid (APMA), and an inhibitory metalloproteinase substrate analogue U27391 were tested for their ability to modulate rhIL-1 beta-induced GAG loss and GAG synthesis ([35S]O4 uptake) inhibition. As expected 1,10-phenanthroline inhibited GAG loss, however [35S]O4 incorporation was significantly reduced. TLCK was without effect, and APMA inhibited both parameters. U27391 reversed both the inhibition of [35S]O4 incorporation and GAG loss. It is concluded that the adverse effects on proteoglycan metabolism explain the inhibitory actions of 1,10-phenanthroline and APMA, whilst the action of TLCK may indicate that serine proteinases are not involved in the activation of latent metalloproteinase. U27391 exhibited chondroprotective activity and confirmed the induction of either metalloproteinases such as stromelysin or collagenase by rhIL-1 beta.
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Roussel Laboratories Limited, Swindon, Wilts, UK.
Thomson
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Gardner
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D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism*; D005270:Femur Head / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011509:Proteoglycans / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000494:pharmacology; D013462:Sulfur Radioisotopes
D007375:Interleukin-1; D011509:Proteoglycans; D011994:Recombinant Proteins; D013462:Sulfur Radioisotopes; D008666:Metalloendopeptidases