CHONDROPROTECTIVE EFFECT OF INTRAARTICULAR INJECTIONS OF INTERLEUKIN-1 RECEPTOR ANTAGONIST IN EXPERIMENTAL OSTEOARTHRITIS - SUPPRESSION OF COLLAGENASE-1 EXPRESSION

Objective. To investigate the in vivo effect of recombinant human inte rleukin-1 receptor antagonist (rHuIL-1Ra) on the development of lesion s and the expression of metalloproteases in the canine experimental os teoarthritis (OA) model.Methods. The right anterior cruciate ligament was sectioned percutaneously in 3 groups of dogs. The control group (n = 5) received an intraarticular injection of sterile physiologic sali ne (1 ml) twice weekly for 4 weeks starting on the day of surgery. The remaining 2 groups received intraarticular injections of either 2 mg (n = 6) or 4 mg (n = 5) rHuIL-1Ra in 1 ml of physiologic saline accord ing to the same schedule as the first group. All dogs were killed 4 we eks after surgery. The macroscopic appearance of femoral condyle osteo phytes and the size and severity of cartilage lesions on femoral condy les and tibial plateaus were evaluated, as were the histologic feature s of cartilage and synovial membrane. Levels of collagenase-1 and stro melysin-1 messenger RNA expression in cartilage and synovium were dete rmined by Northern blotting. Results. Recombinant human IL-1Ra exerted a dose-dependent protective effect on the development of osteophytes and cartilage lesions in vivo. Treatment with rHuIL-1Ra reduced the in cidence (saline-treated group 70%, 2 mg rHuIL-1Ra-treated group 42%, 4 mg rHuIL-1Ra-treated group 20%) and size (saline-treated group 2.3 +/ - 0.7 mm [mean +/- SEM], 2 mg rHuIL-1Ra-treated group 0.7 +/- 0.3 mm, 4 mg rHuIL-1Ra-treated group 0.5 + 0.3 mm) of femoral condyle osteophy tes. In addition, a dose-dependent decrease in the size (saline-treate d group 24.40 +/- 8.17 mm(2), 2 mg rHuIL-1Ra-treated group 20.90 +/- 8 .01 mm(2), 4 mg rHuIL-1Ra-treated group 7.70 +/- 5.16 mm(2)) and the g rade (0-4 scale; saline-treated group 1.20 +/- 0.29, 2 mg rHuIL-1Ra-tr eated group 1.00 +/- 0.26, 4 mg rHuIL-1Ra-treated group 0.30 +/- 0.21) of the tibial plateau cartilage lesions was found, with a significant difference (P < 0.04) reached only with 4 mg rHuIL-1Ra. Similarly, th e histologic lesions in dogs treated with 4 mg rHuIL-1Ra (Mankin scale ; mean +/- SEM 2.95 +/- 0.53) were significantly less severe (P < 0.00 2) compared with those in the saline-treated group (4.95 +/- 0.54). Im portantly, rHulL-1Ra treatment led to a significant reduction (P < 0.0 05) of collagenase-1 expression in OA cartilage. Conclusion. This stud y demonstrated that intraarticular injections of rHuIL-1Ra can protect against the development of experimentally induced OA lesions. This ef fect could result, at least in part, from a reduction of collagenase-1 expression. However, other catabolic processes involved in the degrad ation of OA cartilage may also be affected.