The impact of early intra-articular administration of interleukin-1 receptor antagonist on lubricin metabolism and cartilage degeneration in an anterior cruciate ligament transection model

Abstract

Study the impact of intra-articular interleukin-1 receptor antagonist (IL-1 ra) treatment onlubricin biosynthesis following anterior cruciate ligament transection (ACLT) in the rat and evaluate the effect of combined IL-1 ra and recombinant human lubricin (rhPRG4) treatments on chondrocyte apoptosis. ACLT was performed in male Lewis rats. Treatments included IL-1 ra or vehicle (n=36 in each group). IL-1 ra intra-articular dosing was performed on days 1, 3, 5 and 7 following ACLT using Anakinra (150mg/ml; 40μl). At 3 and 5 weeks, animals were sacrificed and RNA was isolated. Histological analyses included Safranin O and H&E. Lubricin synovial fluid (SF) lavage concentrations were determined at 5 weeks. ACLT animals were treated with a single injection of vehicle, IL-1 ra (75mg/ml; 40μl), rhPRG4 (200μg/ml; 40μl), or IL-1 ra+rhPRG4 (75mg/ml+200μg/ml; 40μl) (n=6 in each group) on day 7 following ACLT and cartilage was probed for cleaved caspase-3 at 5 weeks. IL-1 ra treatment improved lubricin expression (P<0.001) and lubricin SF lavage concentrations in the IL-1 ra group was higher (P=0.005) than the vehicle. IL-1 ra treatment reduced cartilage and synovial scores (P<0.001) compared to vehicle. IL-1 ra and rhPRG4 acted synergistically to reduce caspase-3 positive chondrocytes (P<0.001) compared to individual treatments. IL-1 ra treatment preserved lubricin following ACLT and a combined treatment of IL-1 ra+rhPRG4 may act synergistically to reduce cartilage catabolism.