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: