title: Connective tissue growth factor and integrin αvβ6: a new pair of regulators critical for ductular reaction and biliary fibrosis in mice.
abstract: Connective tissue growth factor (CTGF) is a matricellular protein that mediates cell-matrix interaction through various subtypes of integrin receptors. This study investigated the role of CTGF and integrin αvβ6 in hepatic progenitor/oval cell activation, which often occurs in the form of ductular reactions (DRs) when hepatocyte proliferation is inhibited during severe liver injury. CTGF and integrin αvβ6 proteins were highly expressed in DRs of human cirrhotic livers and cholangiocarcinoma. Confocal microscopy analysis of livers from Ctgf promoter-driven green fluorescent protein reporter mice suggested that oval cells and cholangiocytes were the main sources of CTGF and integrin αvβ6 during liver injury induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Deletion of exon 4 of the Ctgf gene using tamoxifen-inducible Cre-loxP system down-regulated integrin αvβ6 in DDC-damaged livers of knockout mice. Ctgf deficiency or inhibition of integrin αvβ6, by administrating the neutralizing antibody, 6.3G9 (10 mg/kg body weight), caused low levels of epithelial cell adhesion molecule and cytokeratin 19 gene messenger RNAs. Also, there were smaller oval cell areas, fewer proliferating ductular epithelial cells, and lower cholestasis serum markers within 2 weeks after DDC treatment. Associated fibrosis was attenuated, as indicated by reduced expression of fibrosis-related genes, smaller areas of alpha-smooth muscle actin staining, and low collagen production based on hydroxyproline content and Sirius Red staining. Finally, integrin αvβ6 could bind to CTGF mediating oval cell adhesion to CTGF and fibronection substrata and promoting transforming growth factor (TGF)-β1 activation in vitro.
  
  
  CONCLUSIONS
  CTGF and integrin αvβ6 regulate oval cell activation and fibrosis, probably through interacting with their common matrix and signal partners, fibronectin and TGF-β1. CTGF and integrin αvβ6 are potential therapeutic targets to control DRs and fibrosis in related liver disease.
authors.affiliation: Departments of Pediatrics, University of Florida, Gainesville, FL.
authors.forename: Liya
authors.initials: L
authors.lastname: Pi
authors.forename: Paulette M
authors.initials: PM
authors.lastname: Robinson
authors.forename: Marda
authors.initials: M
authors.lastname: Jorgensen
authors.forename: Seh-Hoon
authors.initials: SH
authors.lastname: Oh
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Brown
authors.forename: Paul H
authors.initials: PH
authors.lastname: Weinreb
authors.forename: Thu Le
authors.initials: TL
authors.lastname: Trinh
authors.forename: Protopapadakis
authors.initials: P
authors.lastname: Yianni
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Andrew
authors.initials: A
authors.lastname: Leask
authors.forename: Shelia M
authors.initials: SM
authors.lastname: Violette
authors.forename: Edward W
authors.initials: EW
authors.lastname: Scott
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Schultz
authors.forename: Bryon E
authors.initials: BE
authors.lastname: Petersen
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D001650:Bile Duct Neoplasms / Q000378:metabolism; D001653:Bile Ducts, Intrahepatic; D002448:Cell Adhesion; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D018281:Cholangiocarcinoma / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011725:Pyridines; D011817:Rabbits; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; D000951:Antigens, Neoplasm; D005353:Fibronectins; D016023:Integrins; D011725:Pyridines; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; C073878:integrin alphavbeta6; D055513:Connective Tissue Growth Factor