Nitric oxide activates metalloprotease enzymes in articular cartilage.
Nitric oxide (NO.) is a multifunctional messenger molecule generated by a family of enzymes, collectively termed the nitric oxide synthases. We investigated the role of NO. in the modulation of two metal-dependent proteolytic enzymes (collagenase and stromelysin) which are activated during inflammatory and infective arthritis. The inflammatory mediators interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha) and the bacterial cell wall fragment endotoxin, induced both nitric oxide synthase activity and stromelysin and collagenase activity in whole cell preparations and in conditioned media from explants of bovine and human cartilage. Both NO2- (the stable end-product of NO.) and metalloprotease activity were inhibited by competitive inhibitors of nitric oxide synthase. The NO. donor, S-nitroso-N-acetyl-D,L-penicillamine (SNAP) also induced metalloprotease activity in a dose-dependent fashion. These data provide evidence that NO. plays a regulatory role in the activation of metal-dependent proteases in articular chondrocytes and cartilage.
Murrell
G A
GA
Laboratory for Soft Tissue Research, Hospital for Special Surgery, Cornell University Medical College, New York, NY.
Jang
D
D
Williams
R J
RJ
D000594:Amino Acid Oxidoreductases / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002358:Cartilage, Articular / Q000166:cytology / Q000201:enzymology*; D002417:Cattle; D002470:Cell Survival; D002478:Cells, Cultured; D002648:Child; D017364:Collagenases / Q000378:metabolism*; D017077:Culture Media, Conditioned; D004731:Endotoxins / Q000494:pharmacology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007700:Kinetics; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000494:pharmacology*; D019001:Nitric Oxide Synthase; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D017077:Culture Media, Conditioned; D004731:Endotoxins; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D017364:Collagenases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D010396:Penicillamine; D019331:NG-Nitroarginine Methyl Ester