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

Abstract 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....

Full description

Bibliographic Details
Main Authors: Yuko Tokunaga, Yosuke Osawa, Takahiro Ohtsuki, Yukiko Hayashi, Kenzaburo Yamaji, Daisuke Yamane, Mitsuko Hara, Keisuke Munekata, Kyoko Tsukiyama-Kohara, Tsunekazu Hishima, Soichi Kojima, Kiminori Kimura, Michinori Kohara
Format: Article
Language:English
Published: Nature Portfolio 2017-03-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-017-00282-w
_version_ 1818839729105272832
author Yuko Tokunaga
Yosuke Osawa
Takahiro Ohtsuki
Yukiko Hayashi
Kenzaburo Yamaji
Daisuke Yamane
Mitsuko Hara
Keisuke Munekata
Kyoko Tsukiyama-Kohara
Tsunekazu Hishima
Soichi Kojima
Kiminori Kimura
Michinori Kohara
author_facet Yuko Tokunaga
Yosuke Osawa
Takahiro Ohtsuki
Yukiko Hayashi
Kenzaburo Yamaji
Daisuke Yamane
Mitsuko Hara
Keisuke Munekata
Kyoko Tsukiyama-Kohara
Tsunekazu Hishima
Soichi Kojima
Kiminori Kimura
Michinori Kohara
author_sort Yuko Tokunaga
collection DOAJ
description Abstract 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.
first_indexed 2024-12-19T03:58:55Z
format Article
id doaj.art-a5328ca8ed1a462090583dbee4a72a39
institution Directory Open Access Journal
issn 2045-2322
language English
last_indexed 2024-12-19T03:58:55Z
publishDate 2017-03-01
publisher Nature Portfolio
record_format Article
series Scientific Reports
spelling doaj.art-a5328ca8ed1a462090583dbee4a72a392022-12-21T20:36:44ZengNature PortfolioScientific Reports2045-23222017-03-017111110.1038/s41598-017-00282-wSelective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse modelYuko Tokunaga0Yosuke Osawa1Takahiro Ohtsuki2Yukiko Hayashi3Kenzaburo Yamaji4Daisuke Yamane5Mitsuko Hara6Keisuke Munekata7Kyoko Tsukiyama-Kohara8Tsunekazu Hishima9Soichi Kojima10Kiminori Kimura11Michinori Kohara12Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical ScienceDivision of Hepatology, Tokyo Metropolitan Komagome HospitalDepartment of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical ScienceDepartment of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical ScienceDepartment of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical ScienceDepartment of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical ScienceMicro-signaling Regulation Technology Unit, RIKEN Center for Life Science TechnologiesDepartment of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical ScienceTransboundary Animal Diseases Center, Joint Faculty of Veterinary Medicine, Kagoshima UniversityDepartment of Pathology, Tokyo Metropolitan Komagome HospitalMicro-signaling Regulation Technology Unit, RIKEN Center for Life Science TechnologiesDivision of Hepatology, Tokyo Metropolitan Komagome HospitalDepartment of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical ScienceAbstract 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.https://doi.org/10.1038/s41598-017-00282-w
spellingShingle Yuko Tokunaga
Yosuke Osawa
Takahiro Ohtsuki
Yukiko Hayashi
Kenzaburo Yamaji
Daisuke Yamane
Mitsuko Hara
Keisuke Munekata
Kyoko Tsukiyama-Kohara
Tsunekazu Hishima
Soichi Kojima
Kiminori Kimura
Michinori Kohara
Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model
Scientific Reports
title Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model
title_full Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model
title_fullStr Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model
title_full_unstemmed Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model
title_short Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model
title_sort selective inhibitor of wnt β catenin cbp signaling ameliorates hepatitis c virus induced liver fibrosis in mouse model
url https://doi.org/10.1038/s41598-017-00282-w
work_keys_str_mv AT yukotokunaga selectiveinhibitorofwntbcatenincbpsignalingameliorateshepatitiscvirusinducedliverfibrosisinmousemodel
AT yosukeosawa selectiveinhibitorofwntbcatenincbpsignalingameliorateshepatitiscvirusinducedliverfibrosisinmousemodel
AT takahiroohtsuki selectiveinhibitorofwntbcatenincbpsignalingameliorateshepatitiscvirusinducedliverfibrosisinmousemodel
AT yukikohayashi selectiveinhibitorofwntbcatenincbpsignalingameliorateshepatitiscvirusinducedliverfibrosisinmousemodel
AT kenzaburoyamaji selectiveinhibitorofwntbcatenincbpsignalingameliorateshepatitiscvirusinducedliverfibrosisinmousemodel
AT daisukeyamane selectiveinhibitorofwntbcatenincbpsignalingameliorateshepatitiscvirusinducedliverfibrosisinmousemodel
AT mitsukohara selectiveinhibitorofwntbcatenincbpsignalingameliorateshepatitiscvirusinducedliverfibrosisinmousemodel
AT keisukemunekata selectiveinhibitorofwntbcatenincbpsignalingameliorateshepatitiscvirusinducedliverfibrosisinmousemodel
AT kyokotsukiyamakohara selectiveinhibitorofwntbcatenincbpsignalingameliorateshepatitiscvirusinducedliverfibrosisinmousemodel
AT tsunekazuhishima selectiveinhibitorofwntbcatenincbpsignalingameliorateshepatitiscvirusinducedliverfibrosisinmousemodel
AT soichikojima selectiveinhibitorofwntbcatenincbpsignalingameliorateshepatitiscvirusinducedliverfibrosisinmousemodel
AT kiminorikimura selectiveinhibitorofwntbcatenincbpsignalingameliorateshepatitiscvirusinducedliverfibrosisinmousemodel
AT michinorikohara selectiveinhibitorofwntbcatenincbpsignalingameliorateshepatitiscvirusinducedliverfibrosisinmousemodel