Apelin from the Infrapatellar Fat Pad Contributes to Knee Pain in MIA-induced Osteoarthritis Model Rats by Regulating Nerve Growth Factor Expression in the Synovium

OBJECTIVE:Osteoarthritis (OA) is characterized by progressive cartilage loss and is a major cause of chronic pain and disability. The infrapatellar fat pad (IFP) is an adipose tissue that contacts the synovium and is implicated in knee OA pain. However, the molecular mechanisms linking the IFP to pain remain poorly understood. In this study, we explored a potential IFP-derived mediator of knee OA pain. DESIGN:Knee OA was induced in male and female Sprague Dawley rats by the intra-articular monoiodoacetic acid injection, and saline was injected as a control. Pain-related behaviors of MIA model rats were assessed using the Pressure Application Measurement (n = 7) and von Frey tests (n = 6-7). RNA sequencing was performed on IFP tissue from MIA model and control rats (n = 4). Expression levels of apelin and its receptor APJ were examined using quantitative polymerase chain reaction, and APJ distribution was examined with immunofluorescence. The involvement of apelin and nerve growth factor (NGF) in knee pain was investigated by intra-articular injection of [Pyr1]-apelin-13, the APJ antagonist ML221 and an anti-NGF antibody. RESULTS:Apelin signaling was identified as the most significant pathway relating to differentially expressed genes in the IFP from rats with knee OA. Apelin expression was upregulated in the IFP, and the intra-articular injection of [Pyr1]-apelin-13 caused knee pain (estimated mean difference of -294.8 g and 95% CI of -487.3 to -102.3 g in the PAM test on day 1). APJ expression was markedly increased in synoviocytes of knee OA. The APJ antagonist ML221 alleviated knee OA pain (estimated mean difference of 239.9 g and 95% CI of 125.3-354.6 g in the PAM test on day 1), in association with reduced NGF expression in the synovium. [Pyr1]-apelin-13-induced knee pain was suppressed by anti-NGF antibody (estimated mean difference of 234.9 g and 95% CI of 124.9-344.9 g in the PAM test on day 1). CONCLUSIONS:Our findings indicate that apelin causes knee OA pain by regulating NGF expression in the synovium of MIA model rats. Targeting apelin signaling may therefore provide a novel analgesic therapy for knee OA pain.