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 interleukin-1 receptor antagonist (rHuIL-1Ra) on the development of lesions and the expression of metalloproteases in the canine experimental osteoarthritis (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 saline (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 according to the same schedule as the first group. All dogs were killed 4 weeks after surgery. The macroscopic appearance of femoral condyle osteophytes and the size and severity of cartilage lesions on femoral condyles and tibial plateaus were evaluated, as were the histologic features of cartilage and synovial membrane. Levels of collagenase-1 and stromelysin-1 messenger RNA expression in cartilage and synovium were determined 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 incidence (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 osteophytes. In addition, a dose-dependent decrease in the size (saline-treated group 24.40 +/- 8.17 mm2, 2 mg rHuIL-1Ra-treated group 20.90 +/- 8.01 mm2, 4 mg rHuIL-1Ra-treated group 7.70 +/- 5.16 mm2) and the grade (0-4 scale; saline-treated group 1.20 +/- 0.29, 2 mg rHuIL-1Ra-treated 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, the histologic lesions in dogs treated with 4 mg rHuIL-1Ra (Mankin scale; mean +/- SEM 2.95 +/- 0.53) were significantly less severe (P < 0.002) compared with those in the saline-treated group (4.95 +/- 0.54). Importantly, rHuIL-1Ra treatment led to a significant reduction (P < 0.005) of collagenase-1 expression in OA cartilage.


CONCLUSIONS
This study demonstrated that intraarticular injections of rHuIL-1Ra can protect against the development of experimentally induced OA lesions. This effect could result, at least in part, from a reduction of collagenase-1 expression. However, other catabolic processes involved in the degradation of OA cartilage may also be affected.
Caron
J P
JP
Simard Research Center, Notre-Dame Hospital, Montreal, Quebec, Canada.
Fernandes
J C
JC
Martel-Pelletier
J
J
Tardif
G
G
Mineau
F
F
Geng
C
C
Pelletier
J P
JP
D000818:Animals; D001483:Base Sequence; D017364:Collagenases / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D005270:Femur Head / Q000473:pathology*; D006801:Humans; D007270:Injections, Intra-Articular; D053590:Interleukin 1 Receptor Antagonist Protein; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D010003:Osteoarthritis / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000378:metabolism; D012795:Sialoglycoproteins / Q000008:administration & dosage / Q000032:analysis / Q000494:pharmacology*; D013582:Synovial Fluid / Q000737:chemistry; D013583:Synovial Membrane / Q000473:pathology; D013977:Tibia / Q000473:pathology
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D012333:RNA, Messenger; D012795:Sialoglycoproteins; D017364:Collagenases; D019278:Matrix Metalloproteinase 3