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. CONCLUSION: Pioglitazone and fenofibrate decreased arthritis severity in adjuvant-induced arthritis. Both agonists partially protected animals from inflammatory induced-bone loss.

Concomitant Administration of Rosuvastatin and Lefleunamide in Low doses Synergize Against Complete Freunds Adjuvant (CFA)-Induced Rheumatoid Arthritis in Experimental Model

“…The present work demonstrates that IL-6 level in serum of arthritic animals was highly increased. In agreement with other findings [35,40,41], administration of ROSV significantly decreased the serum IL-6 level in arthritic animals. The serum level of IL-6 was also decreased in arthritic rats treated with LFLU.…”

Protective effects of fenofibrate and resveratrol in an aggressive model of rheumatoid arthritis in rats

“…Histopathological examination of joint and spleen sections strongly supported these findings. In the agreement, Koufany et al (2014) reported that fenofibrate could protect against adjuvant-induced arthritis in rats. Since MMPs are released from activated macrophages during the course of RA, leading to joint destruction and release of COMP into circulation, suppression of MMP-3 and COMP levels strongly indicates inhibition of cartilage destruction (Andersson et al 2013;Kizaki et al 2015).…”

Rheumatoid cachexia: the underappreciated role of myoblast, macrophage and fibroblast interplay in the skeletal muscle niche

“…Treatment with a peroxisome proliferator-activated receptor-α (PPARα) agonist had similar effects, attenuating the decrease in gastrocnemius weight and fast-twitch myofibre size, and preventing the arthritis-induced increase in atrogin-1 and MuRF1 expression in a rodent CIA model [126]. In addition to positive effects in skeletal muscle, PPAR-α also has anti-inflammatory effects and studies have determined that treatment with PPAR-α agonist resulted in reduced oedema and arthritis score in arthritic rodents [127]. However, the use of PPAR agonists are not an option due to their many side effects, including congestive heart failure, bone fractures, liver disease and myopathy [128].…”