Recombinant human protease nexin-1 prevents articular cartilage-degradation in the rabbit.
Cartilage degradation is mediated by activated matrix metalloproteinases (MMP). Since the plasmin/plasminogen cascade may activate latent MMP during cartilage catabolism, we determined if protease nexin-1 (PN-1), an inhibitor of plasminogen, plasmin, and urokinase could prevent cartilage degradation. Using a rabbit model, we induced cartilage glycosaminoglycan (GAG) loss by intraarticular (IA) injection of IL-1 beta and bFGF. PN-1 was given IA for 4 days, once before IL-1 beta/bFGF and daily for 3 days. Three days after IL-1 beta/bFGF, we determined GAG loss. PN-1 significantly inhibited GAG loss at 2.8, 2.5 mg, and 2.0 mg/knee (p < 0.03). These data suggest the role of the plasmin/plasminogen enzymatic cascade in the cartilage catabolism that occurs during IL-1-induced inflammation and demonstrates the potential of PN-1 to prevent cartilage degradation.
Department of Pharmacology, Thousand Oaks, CA.
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P
Stevens
R W
RW
Scott
E M
EM
Shatzen
D016564:Amyloid beta-Protein Precursor; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology*; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism*; D003574:Cytochrome c Group / Q000494:pharmacology; D005341:Fibrinolysin / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007596:Joints / Q000378:metabolism; D015849:Plasminogen Inactivators / Q000494:pharmacology*; D058255:Protease Nexins; D011817:Rabbits; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins / Q000494:pharmacology; D058258:Serpin E2
D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D003574:Cytochrome c Group; D006025:Glycosaminoglycans; D007375:Interleukin-1; D015849:Plasminogen Inactivators; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C545486:SERPINE2 protein, human; D058258:Serpin E2; D016222:Fibroblast Growth Factor 2; D005341:Fibrinolysin