Effects of tenidap on canine experimental osteoarthritis i. morphologic and metalloprotease analysis

Abstract

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 5 0.001) and size (P 5 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 I 0.003) in the tenidap group. Tenidap markedly decreased stromelysin and collagenase activity in both cartilage (stromelysin P I 0.003; collagenase P I 0.01) and synovial membrane (stromelysin P 5 0.003; collagenase P 5 0.005). Moreover, tenidap also decreased the collagenase mRNA level in cartilage (P 5 0.005) and synovial membrane (P 5 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.Conchsion. 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.Transection of the anterior cruciate ligament of the dog knee leads to articular changes which resemble the morphologic and biochemical changes seen in human osteoarthritis (OA) (1-3). Cartilage lesions are probably related to mechanical as well as biochemical factors, including the enzymatic cleavage of matrix macromolecules (4). Matrix metalloproteases (MMP), such as collagenase and stromelysin, have been found to be significantly increased in OA cartilage and synovial membrane, in humans as well as in the experimental dog model (4-6). It is becoming more and more

The peroxisome proliferator–activated receptor γ agonist pioglitazone reduces the development of cartilage lesions in an experimental dog model of osteoarthritis: In vivo protective effects mediated through the inhibition of key signaling and catabolic pathways

“…Lesional joint cartilage in the placebo-treated group exhibited morphologic changes, including cartilage fibrillation and fissures, changes in cellularity, such as cloning and hypocellularity, and loss of Safranin O staining, as previously described (11,20,21) (Figure 2). A decrease in the histologic score of the medial femoral condyles, indicative of a reduced severity of the lesions, was observed in dogs with OA treated with pioglitazone (median histologic score 6.25 [range [3][4][5][6][7][8][9][10][11][12] in the placebo group versus 4.25 [range [3][4][5][6][7] in the 15 mg/day pioglitazone group and 5.5 [range [5][6] in the 30 mg/day pioglitazone group); this difference was sig- nificant following a dosage of 15 mg/day pioglitazone as compared with the placebo group (P Ͻ 0.05).…”

“…At this time, it is not known whether the data obtained from animal model experimentation can be extrapolated to clinical observations. The experimental dog model of ACLT-induced OA has been used extensively for such purposes (20,21,23,(25)(26)(27) and could thus be an exception and serve as a useful tool in the study of human OA. Studies have recently shown that the positive effects of doxycycline on OA structural changes in an experimental dog model of OA (28) could also be seen in patients with knee OA treated with this drug (29).…”

“…Twenty-three adult crossbred dogs (2-3 years old, each weighing 20-25 kg) were used in this study. Surgical sectioning of the ACL of the right knee, through a stab wound, was performed on all dogs as previously described (20). Following surgery, the dogs were housed on a farm, where they had free access to exercise in a large enclosure.…”

“…Cartilage was removed from the areas of the lesions identified on macroscopic evaluation. Histologic evaluation was then performed on sagittal sections of cartilage from the lesional areas of each femoral condyle and each tibial plateau, as previously described (20,21). Specimens were dissected, fixed in TissuFix #2 (Laboratoires Gilles Chaput, Montreal, Quebec, Canada), and embedded in paraffin for histologic evaluation.…”

“…The presence of the different antigens in the cartilage was quantified using our previously reported method (20,21,23), with estimates obtained by determining the number of chondrocytes that stained positive in the entire thickness of cartilage. Three sections from each femoral condyle and each tibial plateau were examined.…”