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

CER2530
2005 Vol.23, N°3
PI 0323, PF 0330
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Abstract

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) - &ggr; 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 -&ggr; in rheumatoid synovial fibroblasts (RSF) from RA patients and analyzed the effects of ligands for PPAR-α and -&ggr; 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 -&ggr; 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.