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 experimen tal osteoarthritis (OA) dog model. The action of tenidap on the activi ty 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 untre ated dogs (group I) were killed, and drug treatments were begun for th e other dogs (groups II and III). 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 exam ination of the severity of the cartilage lesions and synovial inflamma tion was also performed, Activity levels of collagenase, stromelysin, and gelatinase as well as collagenase-1, collagenase-3, and stromelysi n-l messenger RNA were determined in the cartilage, The level of IL-1 activity in the synovial fluid was also measured. Results. Among the d ogs with OA, lesions were more severe at 12 weeks than at 4 weeks. Gro up III (tenidap-treated) dogs had a slightly reduced incidence of oste ophytes 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, ten idap decreased the size (condyles 6.00 +/- 2.18 mm(2) versus 21.08 +/- 6.70 mm(2), plateaus 15.50 +/- 4.77 mm(2) versus 35.0 +/- 3.64 mm(2)) 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 car tilage lesions was also decreased in the tenidap-treated dogs versus t he 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 inflamm ation, Tenidap markedly decreased collagenase, stromelysin, and gelati nase activity, as well as the level of expression of collagenase-3 in the cartilage. Interestingly, the activity level of IL-1 in synovial f luid was also significantly reduced in the tenidap-treated dogs. Concl usion. 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 b y the suppressive effect of tenidap on IL-1 activity.