REDUCED PROGRESSION OF EXPERIMENTAL OSTEOARTHRITIS IN-VIVO BY SELECTIVE-INHIBITION OF INDUCIBLE NITRIC-OXIDE SYNTHASE

Objective. To evaluate the in vivo therapeutic efficacy of N-iminoethy l-L-lysine (L-NIL), a selective inhibitor of inducible nitric oxide sy nthase (iNOS), on the progression of lesions in an experimental osteoa rthritis (OA) dog model. The effect of L-NIL on metalloprotease activi ty, levels of interleukin-1 beta (IL-1 beta), prostaglandin E-2 (PGE(2 )), and nitrite/nitrate in synovial fluid was determined. Methods. The OA model was created by sectioning the anterior cruciate ligament of the right stifle joint of mongrel dogs by a stab wound, Dogs were sepa rated into experimental groups: Group 1 was made up of unoperated dogs that received no treatment, group 2 were operated dogs with no treatm ent, and group 3 were operated dogs that received oral L-NIL (10 mg/kg /twice daily) starting immediately after surgery. The OA dogs were kil led at 10 weeks after surgery. Results, Experiments showed that dog OA cartilage explants in culture produced an increased amount of NO (nit rite), Immunohistochemical study demonstrated that this was due to an increased level of iNOS in chondrocytes, OA dogs treated with L-NIL sh owed a reduction in the incidence of osteophytes compared with the unt reated OA dogs (58% versus 92%) as well as in their size (mean +/- SEM 1.92 +/- 0.58 mm versus 5.08 +/- 0.66 mm), Macroscopically, L-NIL dec reased the size of the cartilage lesions by similar to 50% both on con dyles and plateaus, The histologic severity of both the cartilage lesi ons and synovial inflammation was significantly decreased in the L-NIL -treated dogs, Treatment with L-NIL also significantly decreased both collagenase and general metalloprotease activity in the cartilage and the levels of IL-1 beta, PGE(2), and nitrite/nitrate in synovial fluid . Conclusion. This study demonstrated the effectiveness of a selective inhibitor of iNOS, L-NIL, in attenuating the progression of experimen tal OA, The data suggest that L-NIL may act by reducing the activity o f metalloproteases in cartilage and the production of IL-1 beta by syn ovium, both of which are known to play a major role in the pathophysio logy of OA structural changes.