Effects of tenidap on canine experimental osteoarthritis. I. Morphologic and metalloprotease analysis.
OBJECTIVE
To examine the effects of tenidap and diclofenac on osteoarthritic lesions and metalloprotease activity in experimental osteoarthritis (OA).


METHODS
The anterior cruciate ligament of the right stifle joint of 25 mongrel dogs was sectioned by a stab wound. Seven dogs received no treatment, 6 were treated with oral omeprazole (20 mg/day), another 6 were treated with diclofenac (0.25 mg/kg/twice daily) plus omeprazole (20 mg/day), and 6 received oral tenidap (3 mg/kg/twice daily) plus omeprazole (20 mg/day). The dogs received medication for 8 weeks; all dogs were killed at the end of this period. Eight normal dogs were used as controls. Lesions were evaluated macroscopically for the incidence and size of osteophytes and the area and grade of cartilage erosions on the condyles and plateaus, along with histologic evaluation of the severity of the cartilage lesions and synovial inflammation. Stromelysin and collagenase activities and the collagenase messenger RNA (mRNA) level were measured in cartilage and synovial membrane.


RESULTS
Compared with the untreated or omeprazole-treated OA groups, the dogs treated with tenidap exhibited significant reduction in the incidence (P < or = 0.001) and size (P < or = 0.0001) of osteophytes. Tenidap also significantly decreased the size and grade of cartilage macroscopic lesions, as well as the histologic severity of cartilage lesions on both condyles and plateaus. The histologic severity of synovial inflammatory reaction was also significantly reduced (P < or = 0.003) in the tenidap group. Tenidap markedly decreased stromelysin and collagenase activity in both cartilage (stromelysin P < or = 0.003; collagenase P < or = 0.01) and synovial membrane (stromelysin P < or = 0.003; collagenase P < or = 0.005). Moreover, tenidap also decreased the collagenase mRNA level in cartilage (P < or = 0.005) and synovial membrane (P < or = 0.002). Diclofenac slightly reduced the incidence and size of osteophytes and cartilage lesions, but these changes were not statistically significant. Diclofenac had no effect on the severity of synovial inflammation, metalloprotease activity, or collagenase expression.


CONCLUSIONS
This study showed that tenidap had a more potent anti-osteoarthritic effect than diclofenac in this model. The effect of the drug in suppressing metalloprotease synthesis, a process known to play a major role in the pathophysiology of osteoarthritic lesions, may explain its mechanism of action.
Fernandes
J C
JC
University of Montreal, Louis-Charles Simard Research Center, Notre-Dame Hospital, Quebec, Canada.
Martel-Pelletier
J
J
Otterness
I G
IG
Lopez-Anaya
A
A
Mineau
F
F
Tardif
G
G
Pelletier
J P
JP
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D002356:Cartilage / Q000201:enzymology; D017364:Collagenases / Q000378:metabolism*; D004008:Diclofenac / Q000627:therapeutic use; D004285:Dogs; D004359:Drug Therapy, Combination; D005269:Femur / Q000473:pathology; D007211:Indoles / Q000097:blood / Q000627:therapeutic use*; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000378:metabolism*; D009853:Omeprazole / Q000627:therapeutic use; D010003:Osteoarthritis / Q000188:drug therapy* / Q000473:pathology*; D000078183:Oxindoles; D013583:Synovial Membrane / Q000201:enzymology; D013585:Synovitis / Q000201:enzymology / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D000078183:Oxindoles; D004008:Diclofenac; C062866:tenidap; D017364:Collagenases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D009853:Omeprazole