Effect of SOX9 on Ductular Reaction and Fibrogenesis

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Abstract

Background

Ductular reaction (DR), which is induced when self-renewal and regeneration of the liver are damaged, aims to repair and compensate for anatomical and functional loss. DR is also thought to have crucial role in the etiology of fibrosis, and strongly associated with liver diseases, but the pathogenesis is still unknown. Sex determining region Y-box 9 (SOX9) is involved in the organogenesis of several tissues and organs. In the liver, SOX9 has an important function in bile duct generation and liver regeneration. We have studied about an association between DR and SOX9. The aim of this study was to evaluate an effect of SOX9 on DR and liver fibrogenesis and to explore the applicability of treatment of cholestatic liver disease.

Methods

To induce fibrotic reaction by cholestasis and inflammation, we ligated the common bile duct in mice with wild type (WT) and with a liver-specific inactivation of SOX9 (SOX9KO). On day 7 and day 14 after the procedure, liver function tests were performed concurrently with immunohistochemistry and gene expression analyses of liver specimens.

Results

Total bilirubin in WT mice was significantly higher than that in SOX9KO mice on day 7 and day 14, respectively (p<0.01 and p<0.05). Gene expression analysis revealed that the expression of cytokeratin 19, a marker of biliary cells, in SOX9KO mice was significantly lower than that in WT mice on day 14 (p<0.05), and the expression of osteopontin, a marker of biliary cells, in SOX9KO mice was significantly lower than that in WT mice (p<0.05). The expression of Col1A2, a marker of fibrogenesis, in SOX9KO mice showed lower increase rate than that in WT mice.

Conclusion

In the liver damage mice model by common bile duct ligation, SOX9 gene knockout resulted in lower expression of biliary markers and inhibition of DR and fibrogenesis. SOX9 may become a promising molecular target in the treatment of cholestatic liver disease.

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