A new model of osteoarthritis in rabbits

Abstract

A battery of steroidal and nonsteroidal antirheumatic drugs and protease inhibitors were tested by intraarticular injection for effects on osteoarthritis of the knees of rabbits subjected to partial lateral meniscectomy and section of the sesamoid and collateral fibular ligaments. Among the standard drugs, only the glucocorticoid, triamcinolone hexacetonide, and the protease inhibitor, tranexamic acid, exhibited significant anti-osteoarthritic activity. An experimental drug, GPA 2163, also offered some protection against joint degeneration. The nonsteroidal antiinflammatory drugs had no effect on the development of osteoarthritis in the model.In a previous report from this laboratory, a new surgical method for experimental induction of osteoarthritis (OA) in rabbits was described (1). This method, which involves partial lateral meniscectomy and section of the sesamoid and collateral ligaments, induces a relatively consistent and reproducible degenerative disease of rabbit knees in a period of 6 weeks. A battery of selected steroidal drugs, nonsteroidal antiinflammatory drugs (NSAIDs), and other drugs reputed to possess antirheumatic properties or otherwise influence connective tissues have subsequently been tested for systemic efficacy in retarding or reversing the cartilage deterioration in knees of rabbits subjected to the new procedure (2). A few drugs exerted marked to moderate anti-OA activity. These included the steroids, paramethasone and triamcinolone, only 2 of 11 NSAlDs tested (pirprofen and the experimental drug, CGS 5391B), the glucofuranoside derivative, tribenoside, and the anti-estrogen, tamoxifen. The anti-osteoarthritic activity could not be explained in terms of known antiinflammatory or other properties of these drugs.In the present study, additional selected drugs have been tested for possible anti-OA efficacy by direct intraarticular (IA) injection in laterally meniscectomized rabbits. MATERIALS AND METHODSMale New Zealand white rabbits (Hare Farms) weighing approximately 4 kg each were subjected to partial lateral meniscectomy with section of the fibular collateral and sesamoid ligaments or sham operation, as previously described (1). The animals were maintained on a diet of standard rabbit pellets and tap water ad libitum.Intraarticular injections into the knee joint of test drugs or vehicle were given either as a single 0.0s ml dose 7 days post-surgery or as two 0.05 ml doses on days 7 and 14 post-surgery. The injections were made using 0.25-ml glass syringes and 26-gauge one-half-inch needles for soluble drugs or 23-gauge one-half-inch needles for suspensions. The source, dosage, and vehicle used for each test drug are shown in Table 1. One drug, triamcinolone hexacetonide, was also injected periarticularly (PA) in one group of rabbits (i.e., the compound was injected into the soft tissue immediately adjacent to the knee joint).In each rabbit tested, the right (operated) knee was injected with drug, while the left (unoperated) knee was injected with vehicle only, as a test for possible i...

Macroscopic Analyses of the Effects of Hyaluronates and Corticosteroids on Induced Osteoarthritis in Rabbits’ Knees

“…There was no predominance of joint lesions between the lateral and medial tibial compartments in any of the groups ( Table 4 ). In the same way as shown by other studies in the literature, the present study demonstrated that the intra-articular injections of low and high molecular weight glycosaminoglycans and corticosteroid had a protective effect on the chondral bone 5 , 15 , 16 , 17 , 18 . This is also in agreement with the study by Karakurum et al (8) , who compared intra-articular injections of prednisolone with injections of hyaluronic acid, in an experimental osteoarthrosis model in rabbits, and observed that the two drugs administered separately prevented joint degeneration to the same extent, while the effect was boosted when the drugs were administered together.…”

Glucocorticosteroids inhibit degradation in bovine cartilage explants stimulated with concomitant plasminogen and interleukin-1<alpha>

“…Some u-PA and plasmin inhibitors have demonstrated good efficacy in vivo. Transexamic acid [11] and recombinant human protease nexin-1 [12] are active inhibitors of cartilage degradation in animal models, and urinary trypsin inhibitor was reported to be efficacious in human patients with OA [13].…”

“…Thus, it seems that the potent effect of glucocorticosteroids on cartilage protection in vitro during concomitant plasminogen/IL-1 stimulation could be due to suppression of u-PA activity. The in vivo efficacy reported for u-PA/plasmin inhibitors [11][12][13] demonstrates the importance of the fibrinolytic system (u-PA/Plasminogen/Plasmin) as an activator of up-regulated pro-MMPs [16].…”

Plasminogen modulation of IL-1-stimulated degradation in bovine and human articular cartilage explants. The role of the endogenous inhibitors: PAI-1,α 2-antiplasmin,α 1-PI,α 2-macroglobulin and TIMP

“…Several u-PA and plasmin inhibitors have been shown to be effective as potential anti-osteoarthritic agents in vivo. Transexamic acid [42] and recombinant human protease nexin-1 [431 are active inhibitors of degradation in animal models, while urinary trypsin inhibitor was reported to be efficacious in human patients with OA [44].…”