The Peroxisome Proliferator-Activated Receptor gamma Agonist Pioglitazone Preserves Bone Microarchitecture in Experimental Arthritis by Reducing the Interleukin-17-Dependent Osteoclastogenic Pathway

Abstract : ObjectiveTo investigate the effect of pioglitazone on ă inflammation-induced bone loss and changes in bone microarchitecture in ă rats with adjuvant-induced arthritis (AIA), focusing on the contribution ă of interleukin-17 (IL-17) and the balance of RANKL and osteoprotegerin ă (OPG). ă MethodsMale Lewis rats sensitized with Freund's complete adjuvant were ă treated orally for 21 days with 30 mg/kg/day of pioglitazone or vehicle. ă Arthritis severity was evaluated by clinical and histologic examination. ă Bone mineral density (BMD) was assessed by dual x-ray absorptiometry. ă The therapeutic effect of pioglitazone on changes of the bone ă architecture was determined by micro-computed tomography (micro-CT). ă Levels of RANKL, OPG, and IL-17 were determined by serum immunoassay and ă by synovial tissue immunohistochemistry. Messenger RNA for IL-17 and ă retinoic acid receptor-related orphan nuclear receptor t (RORt) was ă evaluated by quantitative reverse transcription-polymerase chain ă reaction and IL-17 promoter activity by gene-reporter assay. ă ResultsMicro-CT analysis revealed that pioglitazone treatment reduced ă arthritis severity and bone erosion scores and increased BMD in ă comparison to vehicle treatment. Cortical bone thickness was preserved, ă although the major beneficial effect of pioglitazone was on indices of ă the trabeculae, especially trabecular separation. Pioglitazone reduced ă the ratio of RANKL to OPG, in both the serum and the inflamed synovium. ă Circulating levels of IL-17 were significantly reduced by pioglitazone ă treatment, as were the percentages of IL-17-positive cells, mainly ă polymorphonuclear cells, in the inflamed synovium. Induction of IL-17 ă was strictly dependent on the binding of RORt to IL-17 promoter, and ă lentiviral overexpression of peroxisome proliferator-activated receptor ă (PPAR) reduced the expression of RORt. ă ConclusionPioglitazone decreased the level of inflammatory bone ă destruction and protected the bone microarchitecture in rats with AIA by ă controlling the circulating and local expression of IL-17, with a ă subsequent decrease in the RANKL-to-OPG ratio. Along with the inhibition ă of RORt expression after PPAR overexpression, these findings provide ă evidence of the major contribution of reduced IL-17/RANKL-dependent ă osteoclastogenesis.
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Arthritis and Rheumatism, Wiley, 2013, 65 (12), pp.3084-3095. 〈10.1002/art.38130〉
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Meriem Koufany, Daniel Chappard, Patrick Netter, Claire Bastien, Georges Weryha, et al.. The Peroxisome Proliferator-Activated Receptor gamma Agonist Pioglitazone Preserves Bone Microarchitecture in Experimental Arthritis by Reducing the Interleukin-17-Dependent Osteoclastogenic Pathway. Arthritis and Rheumatism, Wiley, 2013, 65 (12), pp.3084-3095. 〈10.1002/art.38130〉. 〈hal-01464666〉

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