Inhibition of NK-κB signaling by fenofibrate, a peroxisome proliferator-activated receptor-α ligand, presents a therapeutic strategy for rheumatoid arthritis

Objectives: Inflammatory mediators such as interleukin-6 and tumor necrosis factor-α play an important role in the pathogenesis of rheumatoid arthritis (RA) by promoting chronic inflammation and joint damage. NF-κB is a transcriptional activator of genes for these cytokines. It also plays an important role in the regulation of osteoclast differentiation which plays a key role in joint destruction in RA. Ligands for peroxisome proliferator-activated receptor (PPAR) - γ have recently been reported to inhibit the development of RA. In this study, we investigated the role of PPARα in RA. Methods: We analyzed the protein expression of PPAR-α and -γ in rheumatoid synovial fibroblasts (RSF) from RA patients and analyzed the effects of ligands for PPAR-α and -γ on cytokine production from RSF, NF-κB activations in RSF and osteoclast differentiation from osteocalst progenitor in the peripheral blood. Moreover, we analyzed the effects of oral administration of PPAR-α and -γ ligands on the development of adjuvant-induced arthritis (AIA) in female Lewis rats. Results: We confirmed the expression of PPAR-α in RSF and also demonstrated that fenofibrate, a ligand for PPAR-α, inhibited cytokine production from RSF, NF-κB activation in RSF, and osteoclast differentiation from osteoclast progenitor cells. Furthermore, we demonstrated that fenofibrate inhibits the development of arthritis in a rat model of human RA. Conclusions: These results indicate that fenofibrate suppresses the development of arthritis by inhibition of NF-κB signaling; therefore, this compound offers possible anti-rheumatic drug.