Effects of tenidap on the progression of osteoarthritic lesions in a canine experimental model. Suppression of metalloprotease and interleukin‐1 activity

Abstract

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 I1 (n = 6) was treated with oral omeprazole (20 mg/day), and group I11 (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 I1 and 111). These dogs received medication 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 111 (tenidap-treated) dogs had a slightly reduced incidence of osteophytes compared with the group I1 (12-week OA) dogs (71% versus loo%), and the size of the osteophytes was significantly diminished (mean f SEM 1.75 f 0.69 mm versus 4.38 f 0.64 mm). Macroscopically, tenidap decreased the size (condyles 6.00 +-2.18 mm' versus 21.08 f 6.70 mm', plateaus 15.50 f 4.77 mm' versus 35.0 f 3.64 mm') and the grade (condyles 0.57 & 0.20 versus 1.17 -C 0.21, plateaus 1.07 f 0.22 versus 2.00 2 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 f 0.38) and on the plateaus (3.39 f 0.35 versus 5.54 f 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.Conclusion. 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

COX-2 is associated with cadmium-induced ICAM-1 expression in cerebrovascular endothelial cells

“…It has been previously shown that cyclooxygenase activity accompanied by prostaglandin production could modulate the induction of inflammatory mediators such as cytokines, iNOS and MMP-9 (Minghetti et al, 1996;Fernandes et al, 1997). In the present study, we observed that Cd-induced ICAM-1 expression was significantly attenuated by NSAIDs, which was reversed by addition of exogenous PGE 2 , demonstrating the role of COX-2 in CNS inflammation.…”

In vivo dual inhibition of cyclooxygenase and lipoxygenase by ML-3000 reduces the progression of experimental osteoarthritis: Suppression of collagenase 1 and interleukin-1? synthesis

“…The extent of the effects was similar to that previously demonstrated with intraarticular steroid injections in this model (22,37) and with tenidap (38), an antiinflammatory drug, which potently inhibited COX as well as the synthesis of proinflammatory cytokines including IL-1␤ and IL-6 (39). The inhibition of IL-1␤ synthesis/action seemed to be of particular importance to the effectiveness of these drugs in reducing the development of OA in the dog model (24,40).…”

“…The extent of reduction in the severity of cartilage structural changes induced by ML-3000 in this OA model was similar to that previously reported to occur with tenidap (38). At the histologic level, the effect of the drug was characterized by a significant decrease in the severity of changes for all OA histologic criteria, including cartilage structure, cell morphology, and intensity of Safranin O staining.…”

Immunopathological mechanisms in dogs with rupture of the cranial cruciate ligament

“…Yet, SF IL-1 bioactivity is only found in 8% of the samples (Carter et al, 1999). In dogs with experimentally transected CrCL (Pond-Nuki model), bioactivity of IL-1 varied from undetectable to increased in the operated stifle joints (Carter et al, 1999;Fernandes et al, 1997). Significant higher levels were found by bioassay in the SF of dogs with naturally occurring CrCL rupture compared with SF of normal dogs (Fujita et al, 2006).…”