The chondroprotective drugs, Arteparon and sodium pentosan polysulphate, increase collagenase activity and inhibit stromelysin activity in vitro.
The effects of the chondroprotective drugs, sodium pentosan polysulphate (SP54) and Arteparon (glycosaminoglycan polysulphate), on the in vitro activities of the purified matrix metalloproteinases interstitial collagenase (matrix metalloproteinase 1, MMP1) and stromelysin (MMP3) were examined. Both drugs produced concentration-dependent enhancement of the degradation of type I collagen fibrils by purified human fibroblast collagenase and rat tumour collagenase. Rat collagenase activity was increased by drug concentrations above 0.5 microgram/mL, whereas human collagenase activity was only increased by higher drug concentrations, above 5 micrograms/mL. The concentration dependence of the increase in rat collagenase activity was similar for both drugs, with a maximal 3-fold increase at 50 micrograms/mL. In contrast, human collagenase activity was increased to a greater extent by SP 54 compared to Arteparon, with maximal increases at 5000 micrograms/mL of 6-fold and 2-4-fold, respectively. Both drugs produced concentration-dependent inhibition of the proteoglycan-degrading activity of both human fibroblast stromelysin and rat tumour stromelysin. Rat and human stromelysin activities were inhibited at drug concentrations above 0.005 microgram/mL, with a similar concentration dependence for both drugs. Fifty percent inhibition of rat stromelysin was produced by concentrations of each drug in the 0.5-5 microgram/mL range. The pattern of inhibition of human stromelysin was similar, except that drug concentrations in the 500-5000 micrograms/mL range produced 50% inhibition. The possible modes of action for these drug effects and their possible pharmacological significance are discussed.
Nethery
A
A
Department of Rheumatology, University of Sydney, Royal North Shore Hospital, St Leonards, Australia.
Giles
I
I
Jenkins
K
K
Jackson
C
C
Brooks
P
P
Burkhardt
D
D
Ghosh
P
P
Whitelock
J
J
O'Grady
R L
RL
Welgus
H G
HG
D000818:Animals; D017364:Collagenases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006025:Glycosaminoglycans / Q000494:pharmacology*; D006801:Humans; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000378:metabolism*; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats
D006025:Glycosaminoglycans; D011509:Proteoglycans; D010426:Pentosan Sulfuric Polyester; C010034:Arteparon; D017364:Collagenases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3