Inhibition of NF-kappaB signaling by fenofibrate, a peroxisome proliferator-activated receptor-alpha ligand, presents a therapeutic strategy for rheumatoid arthritis.

OBJECTIVES: Inflammatory mediators such as interleukin-6 and tumor necrosis factor-alpha play an important role in the pathogenesis of rheumatoid arthritis (RA) by promoting chronic inflammation and joint damage. NF-kappaB 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) -gamma have recently been reported to inhibit the development of RA. In this study, we investigated the role of PPARalpha in RA.

METHODS: We analyzed the protein expression of PPAR-alpha and -gamma in rheumatoid synovial fibroblasts (RSF) from RA patients and analyzed the effects of ligands for PPAR-alpha and -gamma on cytokine production from RSF NF-kappaB activations in RSF and osteoclast differentiation from osteocalst progenitor in the peripheral blood. Moreover, we analyzed the effects of oral administration of PPAR-alpha and -gamma ligands on the development of adjuvant-induced arthritis (AIA) in female Lewis rats.

RESULTS: We confirmed the expression of PPAR-alpha in RSF and also demonstrated that fenofibrate, a ligand for PPAR-alpha, inhibited cytokine production from RSF, NF- kappaB 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-kappaB signaling; therefore, this compound offers possible anti-rheumatic drug.