title: The peroxisome proliferator-activated receptor γ agonist pioglitazone preserves bone microarchitecture in experimental arthritis by reducing the interleukin-17-dependent osteoclastogenic pathway.
abstract: OBJECTIVE
  To investigate the effect of pioglitazone on inflammation-induced bone loss and changes in bone microarchitecture in rats with adjuvant-induced arthritis (AIA), focusing on the contribution of interleukin-17 (IL-17) and the balance of RANKL and osteoprotegerin (OPG).
  
  
  METHODS
  Male Lewis rats sensitized with Freund's complete adjuvant were treated orally for 21 days with 30 mg/kg/day of pioglitazone or vehicle. Arthritis severity was evaluated by clinical and histologic examination. Bone mineral density (BMD) was assessed by dual x-ray absorptiometry. The therapeutic effect of pioglitazone on changes of the bone architecture was determined by micro-computed tomography (micro-CT). Levels of RANKL, OPG, and IL-17 were determined by serum immunoassay and by synovial tissue immunohistochemistry. Messenger RNA for IL-17 and retinoic acid receptor-related orphan nuclear receptor γt (RORγt) was evaluated by quantitative reverse transcription-polymerase chain reaction and IL-17 promoter activity by gene-reporter assay.
  
  
  RESULTS
  Micro-CT analysis revealed that pioglitazone treatment reduced arthritis severity and bone erosion scores and increased BMD in comparison to vehicle treatment. Cortical bone thickness was preserved, although the major beneficial effect of pioglitazone was on indices of the trabeculae, especially trabecular separation. Pioglitazone reduced the ratio of RANKL to OPG, in both the serum and the inflamed synovium. Circulating levels of IL-17 were significantly reduced by pioglitazone treatment, as were the percentages of IL-17-positive cells, mainly polymorphonuclear cells, in the inflamed synovium. Induction of IL-17 was strictly dependent on the binding of RORγt to IL-17 promoter, and lentiviral overexpression of peroxisome proliferator-activated receptor γ (PPARγ) reduced the expression of RORγt.
  
  
  CONCLUSIONS
  Pioglitazone decreased the level of inflammatory bone destruction and protected the bone microarchitecture in rats with AIA by controlling the circulating and local expression of IL-17, with a subsequent decrease in the RANKL-to-OPG ratio. Along with the inhibition of RORγt expression after PPARγ overexpression, these findings provide evidence of the major contribution of reduced IL-17/RANKL-dependent osteoclastogenesis.
authors: UMR-7365, CNRS, Université de Lorraine, Vandoeuvre-lès-Nancy, France.
authors: Meriem
authors: M
authors: Koufany
authors: Daniel
authors: D
authors: Chappard
authors: Patrick
authors: P
authors: Netter
authors: Claire
authors: C
authors: Bastien
authors: Georges
authors: G
authors: Weryha
authors: Jean-Yves
authors: JY
authors: Jouzeau
authors: David
authors: D
authors: Moulin
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D008297:Male; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology*; D053244:Osteoprotegerin / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D053245:RANK Ligand / Q000378:metabolism; D011859:Radiography; D051381:Rats; D011917:Rats, Inbred Lew; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D020381:Interleukin-17; D053244:Osteoprotegerin; D047495:PPAR gamma; D053245:RANK Ligand; D045162:Thiazolidinediones; D000077205:Pioglitazone