title: Sphingosine-1-phosphate stimulated connective tissue growth factor expression in human buccal fibroblasts: Inhibition by epigallocatechin-3-gallate.
abstract: OBJECTIVE
  Connective tissue growth factor (CCN2) has been associated with the pathogenesis of various fibrotic diseases, including oral submucous fibrosis (OSF). The chemical constituents of areca nut along with the mechanical trauma cause OSF. The coarse fibers of areca nut injure the mucosa and hence sphingosine-1-phosphate (S1P) is released at the wounded sites. Recent studies have shown that S1P is involved in wound healing and the development of fibrosis. The aims of this study were to investigate the effects of S1P on CCN2 expression in human buccal fibroblasts (HBFs) and identify the potential targets for drug intervention or chemoprevention of OSF.
  
  
  METHODS
  Western blot analyses were used to study the effects of S1P on CCN2 expression and its signaling pathways in HBFs and whether epigallocatechin-3-gallate (EGCG), the main and most significant polyphenol in green tea, could inhibit this pathway.
  
  
  RESULTS
  S1P significantly enhanced CCN2 synthesis in HBFs. This effect can be inhibited by c-Jun NH2-terminal kinase (JNK) inhibitor and extracellular signal-regulated kinase inhibitor but not by P38 mitogen-activated protein kinase inhibitor. Interestingly, EGCG completely blocked S1P-induced CCN2 expression via suppressing S1P-induced JNK phosphorylation.
  
  
  CONCLUSIONS
  S1P released by repetitive mechanical trauma during AN chewing may contribute to the pathogenesis of OSF through upregulating CCN2 expression in HBFs. EGCG could be an adjuvant to the current offered therapy options or the prevention of OSF through suppression of JNK activation.
authors.affiliation: Department of Dentistry, National Taiwan University Hospital, Hsin-Chu Branch, Taipei, Taiwan.
authors.forename: Jenny I-Chun
authors.initials: JI
authors.lastname: Sar
authors.affiliation: Department of Dentistry, National Taiwan University Hospital, Hsin-Chu Branch, Taipei, Taiwan.
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Yang
authors.affiliation: Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Yi-Shin
authors.initials: YS
authors.lastname: Tsai
authors.affiliation: Department of Dentistry, National Taiwan University Hospital, Hsin-Chu Branch, Taipei, Taiwan.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Deng
authors.affiliation: Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Hsin-Ming
authors.initials: HM
authors.lastname: Chen
authors.affiliation: Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Hao-Hueng
authors.initials: HH
authors.lastname: Chang
authors.affiliation: Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: cmsliu@ntu.edu.tw.
authors.forename: Cheing-Meei
authors.initials: CM
authors.lastname: Liu
mesh_terms: D001114:Areca; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D009914:Oral Submucous Fibrosis / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: C526317:CCN2 protein, human; D008246:Lysophospholipids; D055513:Connective Tissue Growth Factor; C060506:sphingosine 1-phosphate; D002392:Catechin; C045651:epigallocatechin gallate; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013110:Sphingosine
keywords: c-Jun NH(2)-terminal kinase; connective tissue growth factor; epigallocatechin-3-gallate; oral submucous fibrosis; sphingosine-1-phosphate