Affiliations: Laboratoire de Pharmacologie et UMR 7561 CNRS‐UHP, Faculté de Médecine, Avenue de la forêt de Haye, BP 184, 54505 Vandœ uvre‐lès‐Nancy, France
Abstract: 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 μM), as a SOD mimetic, we provide evidence that the inhibitory potency of IL‐1β 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 μg 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.
Keywords: Interleukin‐1, chondrocytes, proteoglycans, superoxide, nitric oxide, NO synthase inhibitors
Journal: Biorheology, vol. 39, no. 1-2, pp. 201-214, 2002
