Selective inhibition of inducible nitric oxide synthase in experimental osteoarthritis is associated with reduction in tissue levels of catabolic factors.

作者：J.-P. Pelletier, Viorica Lascau-Coman, Dragan Jovanović, João Carlos Fernandes, Pamela Toy Manning, J.R. Connor, Mark G. Currie, Johanne Martel‐Pelletier · 发表于：PubMed · 年份：1999 · 被引用次数：158 · 研究领域：Osteoarthritis Treatment and Mechanisms、Nitric Oxide and Endothelin Effects、Veterinary Orthopedics and Neurology

OBJECTIVE: We used the experimental dog model of osteoarthritis (OA) to examine the in vivo effects of N-iminoethyl-L-lysine (L-NIL), a selective inhibitor of the inducible nitric oxide synthase (iNOS), on the tissue level and distribution of interleukin-1beta (IL-1beta), collagenase-1, stromelysin-1, cyclooxygenase-2 (COX-2), iNOS and nitrotyrosine, through immunohistochemical and morphometric analysis. METHODS: Cartilage and synovial membrane specimens were obtained from 3 experimental groups of dogs: Group I--unoperated dogs that received no treatment; Group II--dogs subjected to a sectioning of the anterior cruciate ligament of the right knee and given no treatment; and Group III--operated dogs that received oral treatment with L-NIL (10 mg/kg twice daily/po) for 10 weeks starting immediately after surgery. The operated dogs were killed 10 weeks post-surgery. The tissue distributions of IL-1beta, metalloproteases (MMP), COX-2, iNOS and nitrotyrosine were documented by immunohistochemistry using specific antibodies, and quantified by morphometric analysis. RESULTS: In cartilage, the cell scores (percentage of chondrocytes staining positive for the antigen) for iNOS and 3-nitrotyrosine were dramatically enhanced in OA specimens compared to normal (p < 0.0001). However, the cartilage of dogs treated with L-NIL showed significantly lower cell scores for iNOS (p<0.0001, condyle; p<0.001, plateau), nitrotyrosine (p<0.0004; p<0.0001) and COX-2 (p<0.0001; p<0.001) compared to tha...