title: Anti-Inflammatory mechanisms of the proteinase-activated receptor 2-inhibiting peptide in human synovial cells.
abstract: BACKGROUND
  Osteoarthritis (OA) is a degenerative joint disease which affects the entire joint structure, including the synovial membrane. Disease progression was shown to involve inflammatory changes mediated by proteinase-activated receptor (PAR)-2. Previous studies demonstrated that PAR-2 messenger (m)RNA and protein levels increased in OA synovial cells, suggesting that PAR-2 is a potential therapeutic target of the disease.
  
  
  METHODS
  We designed a PAR-2-inhibiting peptide (PAR2-IP) by changing an isoleucine residue in the PAR-2-activating peptide (PAR2-AP), SLIGKV, to alanine, generating the SLAGKV peptide. We used it to test PAR-2-mediated inflammatory responses, including the expressions of cyclooxygenase (COX)-2 and matrix metalloproteinase (MMP)-1 and activation of nuclear factor (NF)-κB in human synovial cells. As a control, expressions of COX-2 and MMP-1 were induced by trypsin at both the mRNA and protein levels.
  
  
  RESULTS
  The PAR2-AP increased the expression of COX-2 more dramatically than that of MMP-1. When we treated cells with the designed PAR2-IP, the trypsin-induced COX-2 level was completely inhibited at a moderate concentration of the PAR2-IP. With further examination of trypsin-induced NF-κB activation, we observed sufficient inhibitory effects of the PAR2-IP in synoviosarcoma cells and primary synovial cells from OA patients.
  
  
  CONCLUSIONS
  Our study suggests that the PAR2-IP inhibits trypsin-induced NF-κB activation, resulting in a reduction in inflammatory COX-2 expression in synovial cells. Application of PAR2-IP is suggested as a potential therapeutic strategy for OA.
authors.affiliation: Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Ta-Liang
authors.initials: TL
authors.lastname: Chen
authors.forename: Yung-Feng
authors.initials: YF
authors.lastname: Lin
authors.forename: Chao-Wen
authors.initials: CW
authors.lastname: Cheng
authors.forename: Shi-Yun
authors.initials: SY
authors.lastname: Chen
authors.forename: Ming-Thau
authors.initials: MT
authors.lastname: Sheu
authors.forename: Ting-Kai
authors.initials: TK
authors.lastname: Leung
authors.forename: Cheng-Hong
authors.initials: CH
authors.lastname: Qin
authors.forename: Chien-Ho
authors.initials: CH
authors.lastname: Chen
mesh_terms: D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010003:Osteoarthritis / Q000188:drug therapy*; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D009842:Oligopeptides; D044464:Receptor, PAR-2; C109968:seryl-leucyl-isoleucyl--glycyl-lysyl-valine; D051546:Cyclooxygenase 2; D014357:Trypsin; D020781:Matrix Metalloproteinase 1