title: Estrogen receptor-related receptor α regulation by interleukin-1β in prostaglandin E(2)- and cAMP-dependent pathways in osteoarthritic chondrocytes.
abstract: OBJECTIVE
  We reported previously that the orphan nuclear receptor, estrogen receptor-related receptor α (ERRα), is expressed in articular chondrocytes and is dysregulated in a mouse model of inflammatory arthritis. The aim of this study, therefore, was to determine whether ERRα is also dysregulated in patients with osteoarthritis (OA).
  
  
  METHODS
  ERRα messenger RNA (mRNA) and protein were quantified in normal and OA cartilage samples and in OA chondrocytes in vitro, with and without short-term treatment with a variety of OA-associated factors and signaling pathway agonists and inhibitors.
  
  
  RESULTS
  ERRα expression was lower in OA than in normal articular cartilage. Interleukin-1β (IL-1β) markedly up-regulated ERRα expression in OA chondrocytes in vitro, and agonist or inhibitor treatment indicated that the up-regulation was dependent on cyclooxygenase 2 (COX-2; NS398), prostaglandin E(2), cAMP (8-bromo-cAMP), and protein kinase A (PKA; KT5720). Treatment with the ERRα inverse agonist XCT790 decreased the expression of SOX9 and the up-regulation of ERRα by IL-1β, suggesting autoregulation of ERRα in the IL-1β pathway. Matrix metalloproteinase 13 (MMP-13) expression was also decreased by treatment with XCT790 plus IL-1β versus IL-1β alone, and the down-regulation of MMP-13 mRNA and protein observed with XCT790 alone suggests that the up-regulation of MMP-13 by IL-1β is ERRα-dependent.
  
  
  CONCLUSIONS
  We report the first evidence that ERRα expression is regulated by IL-1β in COX-2-, cAMP-, and PKA-dependent pathways in OA chondrocytes. We confirmed that SOX9 is an ERRα target gene in human, as in rodent, chondrocytes and identified MMP-13 as a potential new target gene, which suggests that ERRα may both respond to the healing signal and contribute to extracellular degradation in OA cartilage.
authors.affiliation: INSERM U664, Lyon, France. edith.bonnelye@inserm.fr
authors.forename: Edith
authors.initials: E
authors.lastname: Bonnelye
authors.forename: Pascal
authors.initials: P
authors.lastname: Reboul
authors.forename: Nicolas
authors.initials: N
authors.lastname: Duval
authors.forename: Marco
authors.initials: M
authors.lastname: Cardelli
authors.forename: Jane E
authors.initials: JE
authors.lastname: Aubin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002358:Cartilage, Articular / Q000378:metabolism*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism*; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism*; D011458:Prostaglandins E / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D000242:Cyclic AMP; D053583:Interleukin-1beta; D011458:Prostaglandins E; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D055758:SOX9 Transcription Factor; D000097983:ERRalpha Estrogen-Related Receptor; C527932:SOX9 protein, human