Male or female Lewis rats are injected with peptidoglycan-polysaccharide (PGPS) into the tibiotarsal joint of the ankle or knee joint 2 to 3 weeks prior to reactivation. Two to 3 weeks later, following randomization (arthritis day 1), IV reactivation with a sub-athritogenic PGPS dose is performed and inflammation and/or pain assessment via Von Frey fibers or Gait Analysis are made over the following 4 to 15 days. Animals can be reactivated a second or third time post PGPS challenge (time point of reactivation can vary from 12 days to 3 months).
Classically, peptidoglycan-polysaccharide (PGPS) arthritis has been induced by injecting susceptible male or female rats with a single intraperitoneal (IP) injection of sterile aqueous PGPS (25 µg/gram of body weight)1. The disease that results is a chronic relapsing polyarthritis with an acute phase of joint swelling (multiple joints) on days 2 through 5, followed by a diminution of swelling until day 15 when the disease spontaneously reactivates to varying degrees of severity. Over the next 6 to 8 weeks, the disease progresses to severe, chronic deforming arthritis in most animals2. The pathogenesis is not completely understood, however, systemic injection of PGPS results in the sequestration of large quantities of PGPS in the liver and spleen3. The periodic release of PGPS from these organs could then stimulate the repeated episodes.
Another method used to induce a localized, mono-arthritis with characteristics reminiscent of both rheumatic flares and Osteoarthritis, involves local injection of PGPS into the tibiotarsal joint of the ankle or knee joint of male or female rats4. This results in a local inflammatory reaction stimulated by the presence of PGPS, which is subsequently cleared from the local site. This local reaction peaks in severity 24 hours after injection and then gradually subsides over 2 to 3 weeks. Intravenous injection of a sub-arthritogenic dose of PGPS results in a reactivation of the local inflammation. This rendition of the model allows control of the reactivation events and generally results in very consistent disease severity.
Caliper measurements of ankle or knee joint width are done on the day of reactivation and continued out to 15 days post reactivation. Quantification of acute and chronic pain response via Von Frey hair fibers or gait analysis can be performed during the course of the local inflammatory reaction. At termination (ankle inflammation model), the tibiotarsal joint is transected at the level of the medial and lateral malleolus for determination of paw weights as another measure of inflammation.
Ankles and knees are given scores of 0 to 5 for inflammation, pannus formation, cartilage damage and bone resorption according to these two methods.
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Various types of anti-arthritic agents have shown activity in the PGPS reactivation model including IL-1, TNFa and p38 kinase inhibitors5, 6, 7.