Potent collagenase inhibitors prevent interleukin-1-induced cartilage degradation in vitro.
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.
Nixon
J S
JS
Research Centre, Roche Products Ltd., Welwyn Garden City, Herts., United Kingdom.
Bottomley
K M
KM
Broadhurst
M J
MJ
Brown
P A
PA
Johnson
W H
WH
Lawton
G
G
Marley
J
J
Sedgwick
A D
AD
Wilkinson
S E
SE
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*
D006877:Hydroxamic Acids; D007375:Interleukin-1; D010721:Phosphinic Acids; D010434:Pepsin A; D018093:Gelatinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D003012:Microbial Collagenase