title: Fenofibrate vs pioglitazone: Comparative study of the anti-arthritic potencies of PPAR-alpha and PPAR-gamma agonists in rat adjuvant-induced arthritis.
abstract: BACKGROUND
  Rheumatoid arthritis is characterized by synovial hyperplasia, inflammatory infiltration, cartilage destruction and juxta-articular as well as generalized bone demineralization. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily which behave as ligand-activated transcription factors in response to endogenous fatty acids and eicosanoids or isotype selective synthetic compounds as fibrates and thiazolidinediones. Beyond their key role in lipid metabolism, increased evidence has shown a role of the three isotypes in inflammatory modulation. We and others demonstrated previously that PPAR-gamma agonists reduced the severity of experimental polyarthritis and the overall inflammatory-induced bone loss.
  
  
  OBJECTIVE
  To compare the anti-arthritic potencies of a PPAR-alpha agonist (fenofibrate, a lipid lowering drug) and a PPAR-gamma agonist (pioglitazone, formerly used as an antidiabetic drug) in rat adjuvant-induced arthritis.
  
  
  METHODS
  Male Lewis rats were sensitized by an intra-dermal injection of 1 mg complete Freund's adjuvant at the basis of the tail and were treated orally for 21 days with fenofibrate 100 mg/kg/day (FENO) or pioglitazone 30 mg/kg/day (PIO), or with vehicle only. Arthritis severity was evaluated by clinical observations (oedema, clinical score, body weight). Global and femoral bone mineral density (BMD), femoral bone mineral content (BMC) were measured by dual-energy X-ray absorptiometry (DEXA) before sensitization and at day 20. Synovial mRNA levels of IL-1beta and IL-6 were determined by real-time RT-PCR.
  
  
  RESULTS
  Administration of fenofibrate (100mg/kg/d) and pioglitazone (30 mg/kg/d) significantly reduced hindpaw oedema and arthritis score. Treatment with fenofibrate exerted a better effect on clinical scoring. DEXA analysis revealed that pioglitazone and fenofibrate treatment to a greater extent, reduced inflammatory-bone loss and increased BMD versus vehicle-treated rats. Finally, we demonstrated that both agonists decreased synovial expression of IL-1beta and IL-6.
  
  
  CONCLUSIONS
  Pioglitazone and fenofibrate decreased arthritis severity in adjuvant-induced arthritis. Both agonists partially protected animals from inflammatory induced-bone loss.
authors.affiliation: Faculté de Médecine, UMR-7365 CNRS, Université de Lorraine (Ingénierie Moléculaire et Physiopathologie Articulaire IMoPA), Biôpole de l'Université de Lorraine, Vandœuvre-lès-Nancy, France.
authors.forename: Meriem
authors.initials: M
authors.lastname: Koufany
authors.affiliation: Faculté de Médecine, UMR-7365 CNRS, Université de Lorraine (Ingénierie Moléculaire et Physiopathologie Articulaire IMoPA), Biôpole de l'Université de Lorraine, Vandœuvre-lès-Nancy, France Pôle Laboratoires, Département de Pharmacologie Clinique et Toxicologie, Centre Hospitalier Régional et Universitaire, Nancy, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Jouzeau
authors.affiliation: Faculté de Médecine, UMR-7365 CNRS, Université de Lorraine (Ingénierie Moléculaire et Physiopathologie Articulaire IMoPA), Biôpole de l'Université de Lorraine, Vandœuvre-lès-Nancy, France.
authors.forename: David
authors.initials: D
authors.lastname: Moulin
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001835:Body Weight; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology*; D008297:Male; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D051381:Rats; D011917:Rats, Inbred Lew; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D047493:PPAR alpha; D047495:PPAR gamma; D045162:Thiazolidinediones; D011345:Fenofibrate; D000077205:Pioglitazone
keywords: Adjuvant arthritis; PPARs; bone; fenofibrate; pioglitazone