Anna Moles1, Núria Tarrats, José C Fernández-Checa, Montserrat Marí. 1. Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Centro de Investigaciones Biomédicas Esther Koplowitz, Hospital Clínic, Barcelona, Spain.
Abstract
UNLABELLED: Cathepsins have been best characterized in tumorigenesis and cell death and implicated in liver fibrosis; however, whether cathepsins directly regulate hepatic stellate cell (HSC) activation and proliferation, hence modulating their fibrogenic potential, is largely unknown. Here, we show that expression of cathepsin B (CtsB) and cathepsin D (CtsD) is negligible in quiescent HSCs but parallels the increase of alpha-smooth muscle actin and transforming growth factor-beta during in vitro mouse HSC activation. Both cathepsins are necessary for HSC transdifferentiation into myofibroblasts, because their silencing or inhibition decreased HSC proliferation and the expression of phenotypic markers of HSC activation, with similar results observed with the human HSC cell line LX2. CtsB inhibition blunted AKT phosphorylation in activated HSCs in response to platelet-derived growth factor. Moreover, during in vivo liver fibrogenesis caused by CCl(4) administration, CtsB expression increased in HSCs but not in hepatocytes, and its inactivation mitigated CCl(4)-induced inflammation, HSC activation, and collagen deposition. CONCLUSION: These findings support a critical role for cathepsins in HSC activation, suggesting that the antagonism of cathepsins in HSCs may be of relevance for the treatment of liver fibrosis.
UNLABELLED: Cathepsins have been best characterized in tumorigenesis and cell death and implicated in liver fibrosis; however, whether cathepsins directly regulate hepatic stellate cell (HSC) activation and proliferation, hence modulating their fibrogenic potential, is largely unknown. Here, we show that expression of cathepsin B (CtsB) and cathepsin D (CtsD) is negligible in quiescent HSCs but parallels the increase of alpha-smooth muscle actin and transforming growth factor-beta during in vitro mouse HSC activation. Both cathepsins are necessary for HSC transdifferentiation into myofibroblasts, because their silencing or inhibition decreased HSC proliferation and the expression of phenotypic markers of HSC activation, with similar results observed with the human HSC cell line LX2. CtsB inhibition blunted AKT phosphorylation in activated HSCs in response to platelet-derived growth factor. Moreover, during in vivo liver fibrogenesis caused by CCl(4) administration, CtsB expression increased in HSCs but not in hepatocytes, and its inactivation mitigated CCl(4)-induced inflammation, HSC activation, and collagen deposition. CONCLUSION: These findings support a critical role for cathepsins in HSC activation, suggesting that the antagonism of cathepsins in HSCs may be of relevance for the treatment of liver fibrosis.
Authors: H Nakanishi; J Zhang; M Koike; T Nishioku; Y Okamoto; E Kominami; K von Figura; C Peters; K Yamamoto; P Saftig; Y Uchiyama Journal: J Neurosci Date: 2001-10-01 Impact factor: 6.167
Authors: D B Kristensen; N Kawada; K Imamura; Y Miyamoto; C Tateno; S Seki; T Kuroki; K Yoshizato Journal: Hepatology Date: 2000-08 Impact factor: 17.425
Authors: M E Guicciardi; J Deussing; H Miyoshi; S F Bronk; P A Svingen; C Peters; S H Kaufmann; G J Gores Journal: J Clin Invest Date: 2000-11 Impact factor: 14.808
Authors: T Knittel; D Kobold; F Piscaglia; B Saile; K Neubauer; M Mehde; R Timpl; G Ramadori Journal: Histochem Cell Biol Date: 1999-11 Impact factor: 4.304
Authors: H Okuyama; Y Shimahara; N Kawada; S Seki; D B Kristensen; K Yoshizato; N Uyama; Y Yamaoka Journal: J Biol Chem Date: 2001-05-09 Impact factor: 5.157
Authors: Ubaldo E Martinez-Outschoorn; Casey Trimmer; Zhao Lin; Diana Whitaker-Menezes; Barbara Chiavarina; Jie Zhou; Chengwang Wang; Stephanos Pavlides; Maria P Martinez-Cantarin; Franco Capozza; Agnieszka K Witkiewicz; Neal Flomenberg; Anthony Howell; Richard G Pestell; Jaime Caro; Michael P Lisanti; Federica Sotgia Journal: Cell Cycle Date: 2010-09-09 Impact factor: 4.534
Authors: Shadi A Esfahani; Pedram Heidari; Melanie H Kucherlapati; Jorge M Ferrer; Raju S Kucherlapati; Umar Mahmood Journal: Am J Nucl Med Mol Imaging Date: 2019-10-15
Authors: Sreelatha Gopinath; Rama Rao Malla; Christopher S Gondi; Kiranmai Alapati; Daniel Fassett; Jeffrey D Klopfenstein; Dzung H Dinh; Meena Gujrati; Jasti S Rao Journal: PLoS One Date: 2010-07-22 Impact factor: 3.240
Authors: Han Chen; Jing Wang; Mei-Xiang Xiang; Yan Lin; Aina He; Chun-Na Jin; Jian Guan; Galina K Sukhova; Peter Libby; Jian-An Wang; Guo-Ping Shi Journal: Cardiovasc Res Date: 2013-06-14 Impact factor: 10.787