Nitric oxide (NO) and cartilage metabolism: NO effects are modulated by superoxide in response to IL-1.
Nitric oxide (NO) is thought to mediate most effects of interleukin-1 (IL-1) on cartilage. In vitro evidence includes the decreased synthesis of extracellular matrix components, the abnormal cell renewal, the decreased production of IL-1 receptor antagonist, the induction of apoptosis and the enhanced sensitivity of chondrocytes to oxidative stress. Studies in NOS2(-/-) mice or administration of NO synthase inhibitors in animal models of joint disorders have confirmed its potent pathophysiological role in cartilage. Using L-NMMA (1 mM), as a NO synthase inhibitor, and CuDips (10 microM), as a SOD mimetic, we provide evidence that the inhibitory potency of IL-1beta on proteoglycan synthesis and its stimulating effect on COX-2 activity depend both on NO and O2-* production. Peroxynitrite formation is further demonstrated by the occurrence of 3-nitrotyrosines in chondrocytes stimulated in vitro with 2.5 ng/ml IL-1 and in femoral condyles of rats injected locally with 1 microg IL-1. Preliminary data suggest that such contribution of reactive oxygen species is not shared in common by IL-17, another NO-producing cytokine. We conclude that superoxide is a key modulator of NO-mediated effects in chondrocyte stimulated with IL-1 and that a combined therapy with NO synthase inhibitors and antioxidants may be promising for a full cartilage protection.
Jouzeau
Jean-Yves
JY
Laboratoire de Pharmacologie et UMR 7561 CNRS-UHP, Faculté de Médecine, Vandoeuvre-lès-Nancy, France. jouzeau@facmed.u-nancy.fr
Pacquelet
Sandrine
S
Boileau
Christelle
C
Nedelec
Emmanuelle
E
Presle
Nathalie
N
Netter
Patrick
P
Terlain
Bernard
B
D000818:Animals; D002357:Cartilage Diseases / Q000276:immunology / Q000378:metabolism; D002358:Cartilage, Articular / Q000378:metabolism*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D003864:Depression, Chemical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D020381:Interleukin-17 / Q000494:pharmacology; D008297:Male; D023421:Models, Animal; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011509:Proteoglycans / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D012459:Salicylates / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007375:Interleukin-1; D020381:Interleukin-17; D011509:Proteoglycans; D012459:Salicylates; C030865:copper bis(3,5-diisopropylsalicylate); D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase