Koufany Meriem, Jouzeau Jean-Yves, Moulin David
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.
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.
Biomed Mater Eng. 2014;24(1 Suppl):81-8. doi: 10.3233/BME-140977.
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.
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.
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.
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.
Pioglitazone and fenofibrate decreased arthritis severity in adjuvant-induced arthritis. Both agonists partially protected animals from inflammatory induced-bone loss.
类风湿性关节炎的特征为滑膜增生、炎症浸润、软骨破坏以及关节周围和全身性骨质脱矿质。过氧化物酶体增殖物激活受体（PPARs）是核激素受体超家族的成员，作为配体激活的转录因子，对内源性脂肪酸和类花生酸或如贝特类药物和噻唑烷二酮类的同型选择性合成化合物作出反应。除了在脂质代谢中的关键作用外，越来越多的证据表明这三种同型在炎症调节中也发挥作用。我们和其他人之前已证明，PPAR-γ激动剂可降低实验性多关节炎的严重程度以及炎症诱导的总体骨质流失。
比较PPAR-α激动剂（非诺贝特，一种降脂药物）和PPAR-γ激动剂（吡格列酮，曾用作抗糖尿病药物）在大鼠佐剂性关节炎中的抗关节炎效力。
雄性Lewis大鼠在尾部基部皮内注射1mg完全弗氏佐剂致敏，并分别用100mg/kg/天的非诺贝特（FENO）或30mg/kg/天的吡格列酮（PIO）或仅用赋形剂口服治疗21天。通过临床观察（水肿、临床评分、体重）评估关节炎严重程度。在致敏前和第20天，通过双能X线吸收法（DEXA）测量全身和股骨骨密度（BMD）、股骨骨矿物质含量（BMC）。通过实时RT-PCR测定滑膜中IL-1β和IL-6的mRNA水平。
给予非诺贝特（100mg/kg/d）和吡格列酮（30mg/kg/d）可显著减轻后爪水肿和关节炎评分。非诺贝特治疗对临床评分的效果更好。DEXA分析显示，与赋形剂处理的大鼠相比，吡格列酮和非诺贝特治疗在更大程度上减少了炎症性骨质流失并增加了骨密度。最后，我们证明两种激动剂均降低了滑膜中IL-1β和IL-6的表达。
吡格列酮和非诺贝特可降低佐剂性关节炎的严重程度。两种激动剂均部分保护动物免受炎症诱导的骨质流失。
