title: Potent collagenase inhibitors prevent interleukin-1-induced cartilage degradation in vitro.
abstract: The matrix metalloproteinases (MMPs) collagenase, gelatinase and stromelysin, contribute to the destruction of articular cartilage which occurs during rheumatoid and osteoarthritis. Ro 31-4724, a substrate analogue containing a hydroxamic acid function, is a potent but non-selective inhibitor of all three MMPs (I50, collagenase = 10 nM), whereas Ro 31-7467, a phosphinic acid transition-state analogue, shows 14-fold and 12-fold selectivity for collagenase (I50 = 17 nM) over gelatinase and caseinase (stromelysin) respectively. The effects of these inhibitors on interleukin-1-induced bovine nasal cartilage degradation were examined. The hydroxamate Ro 31-4724 inhibits proteoglycan and collagen loss, whereas the phosphinic acid Ro 31-7467 selectively inhibits collagen breakdown in this model. This represents the first demonstration of potent and selective inhibition of IL1-induced cartilage degradation in vitro by MMP inhibitors. These results suggest that collagenase is responsible for collagen loss and that a different enzyme, possibly stromelysin, is responsible for proteoglycan degradation in this model.
authors.affiliation: Research Centre, Roche Products Ltd., Welwyn Garden City, Herts., United Kingdom.
authors.forename: J S
authors.initials: JS
authors.lastname: Nixon
authors.forename: K M
authors.initials: KM
authors.lastname: Bottomley
authors.forename: M J
authors.initials: MJ
authors.lastname: Broadhurst
authors.forename: P A
authors.initials: PA
authors.lastname: Brown
authors.forename: W H
authors.initials: WH
authors.lastname: Johnson
authors.forename: G
authors.initials: G
authors.lastname: Lawton
authors.forename: J
authors.initials: J
authors.lastname: Marley
authors.forename: A D
authors.initials: AD
authors.lastname: Sedgwick
authors.forename: S E
authors.initials: SE
authors.lastname: Wilkinson
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D018093:Gelatinases; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000502:physiology; D003012:Microbial Collagenase / Q000037:antagonists & inhibitors* / Q000502:physiology; D010434:Pepsin A / Q000502:physiology; D010721:Phosphinic Acids / Q000494:pharmacology*
chemical_list: D006877:Hydroxamic Acids; D007375:Interleukin-1; D010721:Phosphinic Acids; D010434:Pepsin A; D018093:Gelatinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D003012:Microbial Collagenase