title: Prostaglandin EP2 receptor signalling inhibits the expression of matrix metalloproteinase 13 in human osteoarthritic chondrocytes.
abstract: OBJECTIVE
  Matrix metalloproteinase (MMP) 13 is a pathogenic collagenase that causes cartilage destruction and plays a leading role in causing osteoarthritis. This study focused on 114 genes that are differentially expressed between intact and damaged osteoarthritis cartilage, in order to determine which molecules are involved in suppressing MMP-13 expression.
  
  
  METHODS
  MMP-13 concentrations were measured in the supernatant of human osteoarthritis chondrocyte cultures transfected with small interfering RNA (siRNA) against the 114 genes. MMP-13 levels changed most dramatically in response to siRNA against prostaglandin EP2 receptor. The authors performed further measurements of MMP-13 production in osteoarthritis chondrocytes stimulated by the EP2 agonist butaprost in the presence or absence of interleukin-1β (IL-1β) and/or cyclooxygenase-2 (COX-2) inhibitor. They also assessed the effect of butaprost on chondrocyte viability, and investigated the involvement of the cAMP-protein kinase A (PKA) pathway on EP2 signalling using inhibitors. Cartilage-related gene expression was examined in chondrocytes treated with butaprost. The authors also investigated which E series of prostaglandin (EP) receptors are expressed in osteoarthritis cartilage.
  
  
  RESULTS
  MMP-13 messenger RNA expression was significantly affected by two molecules, EP2 receptor and SLC14A1, a urea transporter. In IL-1β-treated osteoarthritis chondrocytes, butaprost suppressed MMP-13 production, which was further decreased by COX-2 inhibitor. EP2 signalling downregulated MMP-13 mRNA expression via the cAMP-PKA pathway without affecting cell viability. Although EP2 signalling enhanced IL-6 expression, the expressions of several catabolic factors (MMP-1, MMP-3, MMP-13, ADAMTS5, IL-1β and tumour necrosis factor alpha) were inhibited. EP2 receptor was the major EP receptor in osteoarthritis cartilage.
  
  
  CONCLUSIONS
  The results suggest that EP2 signalling has 'anti-catabolic' effects in osteoarthritis chondrocytes.
authors.affiliation: Institute of Medical Science, St Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Sato
authors.forename: Koji
authors.initials: K
authors.lastname: Konomi
authors.forename: Ryoji
authors.initials: R
authors.lastname: Fujii
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aono
authors.forename: Satoko
authors.initials: S
authors.lastname: Aratani
authors.forename: Naoko
authors.initials: N
authors.lastname: Yagishita
authors.forename: Natsumi
authors.initials: N
authors.lastname: Araya
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yudoh
authors.forename: Moroe
authors.initials: M
authors.lastname: Beppu
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Yamano
authors.forename: Kusuki
authors.initials: K
authors.lastname: Nishioka
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nakajima
mesh_terms: D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D002358:Cartilage, Articular / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D019902:Chondrocytes / Q000201:enzymology* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis* / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics; D020370:Osteoarthritis, Knee / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000096982:Urea Transporters
chemical_list: D000527:Alprostadil; D053583:Interleukin-1beta; D053509:Matrix Metalloproteinase 13; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D000096982:Urea Transporters; C048491:butaprost