Gait and Behavior in an IL-1-Mediated Model of Rat Knee Arthritis and Effects of an IL1 Antagonist

Abstract

Objective: Interleukin-1 beta (IL1β) is a pro-inflammatory cytokine that mediates arthritic pathologies. Our objective was to evaluate pain and limb dysfunction resulting from IL1β over-expression in the rat knee and investigate the ability of local IL1 receptor antagonist (IL1Ra) delivery to reverse associated pathology.

Design: IL1β over-expression was induced in the right knees of 30 Wistar rats via intra-articular injection of rat fibroblasts retrovirally infected with human IL1β cDNA. A subset of animals received a 30 µL intra-articular injection of saline or human IL1Ra on day 1 after cell delivery (0.65 µg/µL hIL1Ra, n=7 per group). Joint swelling, gait, and sensitivity were investigated over 1 week. On day 8, animals were sacrificed and joints were collected for histological evaluation.

Results: Joint inflammation and elevated levels of endogenous IL1β were observed in knees receiving IL1β infected fibroblasts. Asymmetric gaits favoring the affected limb and heightened mechanical sensitivity (allodynia) reflected a unilateral pathology. Histopathology revealed cartilage loss on the femoral groove and condyle of affected joints. Intra-articular IL1Ra injection failed to restore gait and sensitivity to pre-operative levels and did not reduce cartilage degeneration observed in histopathology.

Conclusion: Joint swelling and degeneration subsequent to IL1β over-expression is associated limb hypersensitivity and gait compensation. Intra-articular IL1Ra delivery did not result in marked improvement for this model; this may be driven by rapid clearance of administered IL1Ra from the joint space. These results motivate work to further investigate the behavioral consequences of monoarticular arthritis and sustained release drug delivery strategies for the joint space.