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.
Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan.
Yuko
Y
Tokunaga
Division of Hepatology, Tokyo Metropolitan Komagome Hospital, Bunkyo-ku, Tokyo, Japan.
Yosuke
Y
Osawa
Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan.
Takahiro
T
Ohtsuki
Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan.|Department of Pathology, Tokyo Metropolitan Komagome Hospital, Bunkyo-ku, Tokyo, Japan.
Yukiko
Y
Hayashi
Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan.
Kenzaburo
K
Yamaji
Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan.
Daisuke
D
Yamane
Micro-signaling Regulation Technology Unit, RIKEN Center for Life Science Technologies, Saitama, Japan.
Mitsuko
M
Hara
Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan.
Keisuke
K
Munekata
Transboundary Animal Diseases Center, Joint Faculty of Veterinary Medicine, Kagoshima University, 1-21-24 Korimoto, Kagoshima, 890-0065, Japan.
Kyoko
K
Tsukiyama-Kohara
Department of Pathology, Tokyo Metropolitan Komagome Hospital, Bunkyo-ku, Tokyo, Japan.
Tsunekazu
T
Hishima
Micro-signaling Regulation Technology Unit, RIKEN Center for Life Science Technologies, Saitama, Japan.
Soichi
S
Kojima
Division of Hepatology, Tokyo Metropolitan Komagome Hospital, Bunkyo-ku, Tokyo, Japan. kkimura@cick.jp.
Kiminori
K
Kimura
Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan. kohara-mc@igakuken.or.jp.
Michinori
M
Kohara
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage*; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D019698:Hepatitis C, Chronic / Q000150:complications*; D006651:Histocytochemistry; D007274:Injections, Intraperitoneal; D008103:Liver Cirrhosis / Q000473:pathology*; D008822:Mice, Transgenic; D011744:Pyrimidinones / Q000008:administration & dosage*; D016896:Treatment Outcome; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000037:antagonists & inhibitors*
D019086:Bridged Bicyclo Compounds, Heterocyclic; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; C492448:ICG 001; D011744:Pyrimidinones; D051176:beta Catenin