Inhibition of NF-kappaB signaling by fenofibrate, a peroxisome proliferator-activated receptor-alpha ligand, presents a therapeutic strategy for rheumatoid arthritis.
OBJECTIVE
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.
Okamoto
H
H
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan. hokamoto@parkcity.ne.jp
Iwamoto
T
T
Kotake
S
S
Momohara
S
S
Yamanaka
H
H
Kamatani
N
N
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology* / Q000627:therapeutic use; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008024:Ligands; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047493:PPAR alpha / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D018501:Antirheumatic Agents; D000960:Hypolipidemic Agents; D008024:Ligands; D016328:NF-kappa B; D047493:PPAR alpha; D047495:PPAR gamma; D011345:Fenofibrate