Nitric oxide and proteoglycan turnover in rabbit articular cartilage.
Articular chondrocytes are known to synthesize large amounts of nitric oxide in response to exposure to interleukin-1, but the role of this radical in proteoglycan turnover remains controversial. In this study, we used two different inhibitors of nitric oxide synthase, NG-methyl-L-arginine and thiocitrulline, to study the effects of nitric oxide on the synthesis and breakdown of proteoglycan in rabbit articular cartilage. Synthesis of nitric oxide by cartilage slices in response to treatment with interleukin-1 and a partially purified mixture of synovial cytokines known as chondrocyte-activating factors peaked during the first 2 days of culture and then fell to low levels, despite daily replenishment with fresh medium and cytokines to the cultures. The production of nitric oxide was completely inhibited by NG-methyl-L-arginine and thiocitrulline. Interleukin-1 and the chondrocyte-activating factors inhibited proteoglycan synthesis and accelerated proteoglycan breakdown in the slices of cartilage. Both nitric oxide synthase inhibitors substantially counteracted the suppression of proteoglycan synthesis but exacerbated proteoglycan catabolism occurring in response to interleukin-1 and the chondrocyte-activating factors. The accelerated catabolism was associated with increased levels of matrix metalloproteinases in the conditioned medium. This dual effect of nitric oxide complicates decision making with regard to the possible clinical applications of nitric oxide agonists or antagonists in diseases of cartilage.
Stefanovic-Racic
M
M
Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pennsylvania, USA.
Möllers
M O
MO
Miller
L A
LA
Evans
C H
CH
D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000201:enzymology*; D002956:Citrulline / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006418:Heme / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011509:Proteoglycans / Q000096:biosynthesis / Q000378:metabolism*; D011817:Rabbits; D013481:Superoxides / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007375:Interleukin-1; D011509:Proteoglycans; C086715:thiocitrulline; D013481:Superoxides; D002956:Citrulline; D009569:Nitric Oxide; D006418:Heme; D019001:Nitric Oxide Synthase; D008666:Metalloendopeptidases; D013890:Thiourea; D019331:NG-Nitroarginine Methyl Ester