Chondroprotective effect of intraarticular injections of interleukin‐1 receptor antagonist in experimental osteoarthritis. Suppression of collagenase‐1 expression

Abstract

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 IGlRa 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 Conclusion. 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.Osteoarthritis (OA) is the most common rheumatic disease and is characterized by progressive depletion of articular cartilage matrix macromolecules. Accumulating evidence suggests that an important component of the matrix loss process is related to activity of proteolytic enzymes which degrade the principal matrix

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

“…It is important to note that we have already observed similar differences when testing the effects of other drugs in this model (20,21,26,27). Although the exact reason for these differences remains unknown, it is likely that the effectiveness of the drugs on the different pathophysiologic mechanisms of OA may vary between the condyles and the plateaus.…”

“…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).…”

Dual transduction of insulin‐like growth factor‐I and interleukin‐l receptor antagonist protein controls cartilage degradation in an osteoarthritic culture model

“…Intraarticular expression has also been confirmed after ex vivo transfer of the IL1Ra gene [2], and for several weeks following in vivo delivery of the adenoviral IL-1 Ra construct [l 11. In vivo, IL-I Ra has been shown to preserve articular cartilage, having beneficial effects on the histology of the synovial membrane, along with decreased pain and generalized joint disease [5,11,17,29].…”

Development and characterization of a fusion protein between thermally responsive elastin‐like polypeptide and interleukin‐1 receptor antagonist: Sustained release of a local antiinflammatory therapeutic

“…Local delivery of IL-1Ra into the joint space has been evaluated in a canine model of OA, with twice weekly intraarticular injections of 2 mg or 4 mg of protein being found to be chondroprotective (14). The safety of intraarticular IL-1Ra delivery has also been demonstrated in human clinical trials using single injections of 150 mg (15).…”