The Journal of Bone and Joint Surgery 78:265-74 (1996)
© 1996 The Journal of Bone and Joint Surgery, Inc.
Nitric Oxide: an Important Articular Free Radical*
GEORGE A. C. MURRELL, M.B.B.S., D.PHIL. ,
MARTIN M. DOLAN, B.A. ,
DANIEL JANG, B.SC.,
CSABA SZABO, M.D., PH.D. ,
RUSSELL F. WARREN, M.D. and
JO A. HANNAFIN, M.D.PH.D., NEW YORK, N.Y.
Investigation performed at the Laboratory for Soft Tissue Research and Sports Medicine Service, The Hospital for Special Surgery, New York City
Nitric oxide is a small molecule that is synthesized by a family of enzymes, the nitric oxide synthases, and is overproduced in rheumatoid arthritis and osteoarthrosis. The aim of this investigation was to elucidate the potential sources of nitric oxide in joint tissues and to determine if the production of nitric oxide could be inhibited by dexamethasone or methotrexate, two agents that inhibit other forms of inducible nitric oxide synthase. Methotrexate inhibits the synthesis of biopterin, which is a co-factor for nitric oxide synthase.
Explants of human and bovine cartilage and cultured chondrocytes released large amounts of nitrite, the stable end product of nitric oxide, when stimulated with endotoxin, interleukin-1ß, or tumor necrosis factor- . The production of nitrite was time-dependent and endotoxin, interleukin-1ß, and tumor necrosis factor- dose-dependent and was inhibited by the nitric-oxide-synthase inhibitors N -nitro-L-arginine methyl ester and aminoguanidine. The inducible nitric oxide synthase in bovine chondrocytes was calcium-dependent and was inhibited by high concentrations of methotrexate or dexamethasone. No constitutive nitric-oxide-synthase activity and little or no inducible nitric-oxide-synthase activity were demonstrable in explants or cell cultures derived from menisci. Fresh explants of bovine articular synovial tissue constitutively released nitrite that was inhibited by N-nitro-L-arginine methyl ester, but the release could not be enhanced by endotoxin, interleukin-1ß, or tumor necrosis factor-. There was no constitutive or inducible production of nitrite by explants or cells derived from the synovial tissue or shoulder capsule of a human or by explants or cells derived from canine anterior cruciate, posterior cruciate, medial collateral, lateral collateral, or patellar ligaments. Taken together, these results indicate that chondrocytes represent the major source of inducible nitric oxide synthase and nitric oxide during inflammation or infection of a joint.
CLINICAL RELEVANCE: Since nitric oxide is a free radical, its effects are extremely rapid, local, and potentially toxic. Induction of high levels of chondrocytic nitric oxide during infection or inflammation may be responsible in part for the damage to cartilage that occurs in some inflammatory arthropathies. Agents that inhibit nitric oxide synthase, especially selective inhibitors of the inducible form of nitric oxide synthase, may offer new and useful means of inhibiting the destruction of cartilage.
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