Effects of tenidap on the progression of osteoarthritic lesions in a canine experimental model. Suppression of metalloprotease and interleukin-1 activity.
OBJECTIVE
To study, in vivo, the therapeutic effectiveness of tenidap, an antirheumatic drug, on the progression of lesions in an experimental osteoarthritis (OA) dog model. The action of tenidap on the activity and expression of metalloproteases in cartilage, as well as on the bioactivity of interleukin-1 (IL-1) in synovial fluid, was determined.


METHODS
The anterior cruciate ligament of the right stifle joint of 20 mongrel dogs was sectioned through a stab wound. Dogs were divided into 3 groups: group I (n = 7) received no treatment, group II (n = 6) was treated with oral omeprazole (20 mg/day), and group III (n = 7) received oral omeprazole (20 mg/day) and a therapeutic dosage of oral tenidap (3 mg/kg twice daily). Four weeks following surgery, the untreated dogs (group I) were killed, and drug treatments were begun for the other dogs (groups II and III). These dogs received medications for 8 weeks (weeks 4-12) and then were killed. Evaluations were made of the incidence and size of osteophytes as well as of the size and grade of cartilage erosions on both the condyles and plateaus. Histologic examination of the severity of the cartilage lesions and synovial inflammation was also performed. Activity levels of collagenase, stromelysin, and gelatinase as well as collagenase-1, collagenase-3, and stromelysin-1 messenger RNA were determined in the cartilage. The level of IL-1 activity in the synovial fluid was also measured.


RESULTS
Among the dogs with OA, lesions were more severe at 12 weeks than at 4 weeks. Group III (tenidap-treated) dogs had a slightly reduced incidence of osteophytes compared with the group II (12-week OA) dogs (71% versus 100%), and the size of the osteophytes was significantly diminished (mean +/- SEM 1.75 +/- 0.69 mm versus 4.38 +/- 0.64 mm). Macroscopically, tenidap decreased the size (condyles 6.00 +/- 2.18 mm2 versus 21.08 +/- 6.70 mm2, plateaus 15.50 +/- 4.77 mm2 versus 35.0 +/- 3.64 mm2) and the grade (condyles 0.57 +/- 0.20 versus 1.17 +/- 0.21, plateaus 1.07 +/- 0.22 versus 2.00 +/- 0.25) of the cartilage lesions compared with the 12-week OA dogs. At the histologic level, the severity of cartilage lesions was also decreased in the tenidap-treated dogs versus the 12-week OA dogs, both on the condyles (3.43 +/- 0.54 versus 5.55 +/- 0.38) and on the plateaus (3.39 +/- 0.35 versus 5.54 +/- 0.60). All 3 OA groups showed a significant and similar level of synovial inflammation. Tenidap markedly decreased collagenase, stromelysin, and gelatinase activity, as well as the level of expression of collagenase-3 in the cartilage. Interestingly, the activity level of IL-1 in synovial fluid was also significantly reduced in the tenidap-treated dogs.


CONCLUSIONS
Tenidap markedly reduced the severity of OA lesions, indicating the effect of this drug in decreasing the progression of disease. It appears that the drug acts by reducing the activity and/or expression of metalloproteases in cartilage, a process known to play a major role in the pathophysiology of OA lesions. This effect could be mediated by the suppressive effect of tenidap on IL-1 activity.
Fernandes
J C
JC
Louis-Charles Simard Research Center, Osteoarthritis Research Unit, Notre-Dame Hospital, Montreal, Quebec, Canada.
Caron
J P
JP
Martel-Pelletier
J
J
Jovanovic
D
D
Mineau
F
F
Tardif
G
G
Otterness
I G
IG
Pelletier
J P
JP
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002358:Cartilage, Articular / Q000201:enzymology; D017364:Collagenases / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D018093:Gelatinases / Q000378:metabolism; D015870:Gene Expression; D007211:Indoles / Q000494:pharmacology*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics; D010003:Osteoarthritis / Q000188:drug therapy / Q000503:physiopathology*; D000078183:Oxindoles; D013582:Synovial Fluid / Q000737:chemistry; D013583:Synovial Membrane / Q000033:anatomy & histology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D007375:Interleukin-1; D000078183:Oxindoles; C062866:tenidap; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3