Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model

Chronic hepatitis C virus (HCV) infection is one of the major causes of serious liver diseases, including liver cirrhosis. There are no anti-fibrotic drugs with efficacy against liver cirrhosis. Wnt/β-catenin signaling has been implicated in the pathogenesis of a variety of tissue fibrosis. In the present study, we investigated the effects of a β-catenin/CBP (cyclic AMP response element binding protein) inhibitor on liver fibrosis. The anti-fibrotic activity of PRI-724, a selective inhibitor of β-catenin/CBP, was assessed in HCV GT1b transgenic mice at 18 months after HCV genome expression. PRI-724 was injected intraperitoneally or subcutaneously in these mice for 6 weeks. PRI-724 reduced liver fibrosis, which was indicated by silver stain, Sirius Red staining, and hepatic hydroxyproline levels, in HCV mice while attenuating αSMA induction. PRI-724 led to increased levels of matrix metalloproteinase (MMP)-8 mRNA in the liver, along with elevated levels of intrahepatic neutrophils and macrophages/monocytes. The induced intrahepatic neutrophils and macrophages/monocytes were identified as the source of MMP-8. In conclusion, PRI-724 ameliorated HCV-induced liver fibrosis in mice. We hypothesize that inhibition of hepatic stellate cells activation and induction of fibrolytic cells expressing MMP-8 contribute to the anti-fibrotic effects of PRI-724. PRI-724 is a drug candidate which possesses anti-fibrotic effect.

[1]  C. Henkel,et al.  Inhibition of hepatic fibrogenesis by matrix metalloproteinase‐9 mutants in mice , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[2]  T. Saibara,et al.  Inhibition of Cyclic Adenosine Monophosphate (cAMP)-response Element-binding Protein (CREB)-binding Protein (CBP)/β-Catenin Reduces Liver Fibrosis in Mice , 2015, EBioMedicine.

[3]  G. Ramm,et al.  Repair after cholestatic liver injury correlates with neutrophil infiltration and matrix metalloproteinase 8 activity. , 2005, Surgery.

[4]  R. Nusse,et al.  The Wnt signaling pathway in development and disease. , 2004, Annual review of cell and developmental biology.

[5]  T. Wynn,et al.  Mechanisms of fibrosis: therapeutic translation for fibrotic disease , 2012, Nature Medicine.

[6]  G. Ramm,et al.  Gastrointestinal , Hepatobiliary and Pancreatic Pathology Neutrophil Depletion Blocks Early Collagen Degradation in Repairing Cholestatic Rat Livers , 2010 .

[7]  D. Brenner,et al.  Erratum: Liver fibrosis (Journal of Clinical Investigation (2005) 115 (209-218) DOI:10.1172/JCI200524282) , 2005 .

[8]  M. Arthur.  Fibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosis. , 2000, American journal of physiology. Gastrointestinal and liver physiology.

[9]  S. Monga,et al.  WNT/beta-catenin signaling in liver health and disease. , 2007, Hepatology.

[10]  M. Arthur.  Metalloproteinases and their inhibitors in liver fibrosis , 2000 .

[11]  A. B. Sukhomlinov,et al.  [Liver cirrhosis]. , 1989, Fel'dsher i akusherka.

[12]  S. Friedman.  Mac the knife? Macrophages- the double-edged sword of hepatic fibrosis. , 2005, The Journal of clinical investigation.

[13]  H. Stein,et al.  In situ hybridization for procollagen types I, III and IV mRNA in normal and fibrotic rat liver: Evidence for predominant expression in nonparenchymal liver cells , 1989, Hepatology.

[14]  H. Tsukamoto,et al.  Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis. , 2008, American journal of physiology. Gastrointestinal and liver physiology.

[15]  Oliver Eickelberg,et al.  WNT signaling in lung disease: a failure or a regeneration signal? , 2010, American journal of respiratory cell and molecular biology.

[16]  M. Kahn,et al.  Targeted inhibition of β-catenin/CBP signaling ameliorates renal interstitial fibrosis. , 2011, Journal of the American Society of Nephrology : JASN.

[17]  K. Matsushima,et al.  Immunization with a Recombinant Vaccinia Virus That Encodes Nonstructural Proteins of the Hepatitis C Virus Suppresses Viral Protein Levels in Mouse Liver , 2012, PloS one.

[18]  R. Nusse,et al.  Wnt signaling in disease and in development , 2005, Cell Research.

[19]  E. Morrisey.  Wnt signaling and pulmonary fibrosis. , 2003, The American journal of pathology.

[20]  S. Monga,et al.  WNT/β‐catenin signaling in liver health and disease , 2007 .

[21]  H. Stein,et al.  Procollagen expression by nonparenchymal rat liver cells in experimental biliary fibrosis. , 1990, Gastroenterology.

[22]  J. Deursen.  The role of senescent cells in ageing , 2014, Nature.

[23]  C. Nguyên,et al.  Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis , 2010, Proceedings of the National Academy of Sciences.

[24]  M. Kahn,et al.  Safely targeting cancer stem cells via selective catenin coactivator antagonism , 2014, Cancer science.

[25]  Y. Hiasa,et al.  Persistent expression of the full genome of hepatitis C virus in B cells induces spontaneous development of B-cell lymphomas in vivo. , 2010, Blood.

[26]  J. Fallowfield,et al.  Edinburgh Research Explorer Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis Differential Ly-6C expression identi fi es the recruited macrophage phenotype, which orchestrates the regression of murine liver fi brosis , 2022 .

[27]  Jinxia Liu,et al.  Truncated Active Human Matrix Metalloproteinase-8 Delivered by a Chimeric Adenovirus-Hepatitis B Virus Vector Ameliorates Rat Liver Cirrhosis , 2013, PloS one.