title: PPARγ agonist rosiglitazone inhibits migration and invasion by downregulating Cyr61 in rheumatoid arthritis fibroblast-like synoviocytes.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have anti-inflammatory properties that reduce inflammatory cytokine production in rheumatoid arthritis (RA). Cysteine-rich angiogenic inducer 61 (Cyr61) is associated with diseases related to chronic inflammation. The aim of this study was to investigate the mechanisms underlying the effects of PPARγ agonists on tumor necrosis factor (TNF)-α-induced fibroblast-like synoviocyte (FLS) invasion and migration, as well as Cyr61 production, in RA-FLS.
  
  
  METHODS
  FLS were cultured with TNF-α and Cyr61 in the presence or absence of PPARγ agonists. Matrix metalloproteinase and Cyr61 expression levels in RA-FLS and culture supernatants were measured by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting. The migration and invasion phenotypes of RA-FLS were determined by wound healing and Boyden chamber assays.
  
  
  RESULTS
  Cyr61 protein was expressed in RA-FLS, and its intracellular expression and secretion levels were increased by TNF-α. Moreover, Cyr61 directly promoted RA-FLS migration and invasion. Rosiglitazone (RSG) significantly decreased TNF-α-induced Cyr61 expression. RSG decreased TNF-α-induced nuclear factor (NF)-κB activation and inhibitor of κBα degradation. Furthermore, RSG inhibited TNF-α-induced RA-FLS migration and invasion and decreased Cyr61 treatment-induced RA-FLS invasion. Finally, blocking Cyr61 significantly attenuated TNF-α-induced migration.
  
  
  CONCLUSIONS
  Our results demonstrate for the first time that PPARγ agonists may have beneficial effects on the migration and invasion of RA-FLS via the downregulation of Cyr61. Therefore, PPARγ agonists could be potential treatment targets for RA.
authors.affiliation: Department of Medicine, Jeju National University School of Medicine, Jeju, Republic of Korea.
authors.forename: Eun-Jeong
authors.initials: EJ
authors.lastname: Kwon
authors.affiliation: Department of Internal Medicine, Jeju National University Hospital, Jeju, Republic of Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Park
authors.affiliation: Department of Orthopedic Surgery, Jeju National University School of Medicine, Jeju, Republic of Korea.
authors.forename: Sungwook
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Orthopedic Surgery, Jeju National University School of Medicine, Jeju, Republic of Korea.
authors.forename: Sang-Rim
authors.initials: SR
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Jeju National University School of Medicine, Jeju, Republic of Korea.
authors.forename: Moonjae
authors.initials: M
authors.lastname: Cho
authors.affiliation: Department of Medicine, Jeju National University School of Medicine, Jeju, Republic of Korea.|Department of Internal Medicine, Jeju National University Hospital, Jeju, Republic of Korea.
authors.forename: Jinseok
authors.initials: J
authors.lastname: Kim
mesh_terms: D018501:Antirheumatic Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010641:Phenotype; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000070918:Synoviocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D045162:Thiazolidinediones / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D018501:Antirheumatic Agents; C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D000072000:NF-KappaB Inhibitor alpha
keywords: cysteine-rich angiogenic inducer 61; peroxisome proliferator-activated receptor gamma; rheumatoid arthritis