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-iminoethyl-L-lysine (L-NIL), a selective inhibitor of inducible nitric oxide synthase (iNOS), on the progression of lesions in an experimental osteoarthritis (OA) dog model. The effect of L-NIL on metalloprotease activity, levels of interleukin-1beta (IL-1beta), prostaglandin E2 (PGE2), 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 separated into experimental groups: Group 1 was made up of unoperated dogs that received no treatment, group 2 were operated dogs with no treatment, and group 3 were operated dogs that received oral L-NIL (10 mg/kg/twice daily) starting immediately after surgery. The OA dogs were killed at 10 weeks after surgery.


RESULTS
Experiments showed that dog OA cartilage explants in culture produced an increased amount of NO (nitrite). Immunohistochemical study demonstrated that this was due to an increased level of iNOS in chondrocytes. OA dogs treated with L-NIL showed a reduction in the incidence of osteophytes compared with the untreated 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 decreased the size of the cartilage lesions by approximately 50% both on condyles and plateaus. The histologic severity of both the cartilage lesions 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-1beta, PGE2, and nitrite/nitrate in synovial fluid.


CONCLUSIONS
This study demonstrated the effectiveness of a selective inhibitor of iNOS, L-NIL, in attenuating the progression of experimental OA. The data suggest that L-NIL may act by reducing the activity of metalloproteases in cartilage and the production of IL-1beta by synovium, both of which are known to play a major role in the pathophysiology of OA structural changes.
Pelletier
J P
JP
Université de Montréal, and Centre Hospitalier de l'Université de Montréal, Quebec, Canada.
Jovanovic
D
D
Fernandes
J C
JC
Manning
P
P
Connor
J R
JR
Currie
M G
MG
Di Battista
J A
JA
Martel-Pelletier
J
J
D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004285:Dogs; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D008666:Metalloendopeptidases / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D009999:Ossification, Heterotopic / Q000517:prevention & control; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology*; D013582:Synovial Fluid / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D004791:Enzyme Inhibitors; D007375:Interleukin-1; D009566:Nitrates; D009573:Nitrites; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D008666:Metalloendopeptidases; D008239:Lysine; D015232:Dinoprostone