Cathepsins B and D drive hepatic stellate cell proliferation and promote their fibrogenic potential

Authors

  • Anna Moles,

    1. Liver Unit, and Centro de Investigaciones Biomédicas Esther Koplowitz, Hospital Clínic and Centro de Investigación Biomédica en Red en el Área de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), and Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain
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  • Núria Tarrats,

    1. Liver Unit, and Centro de Investigaciones Biomédicas Esther Koplowitz, Hospital Clínic and Centro de Investigación Biomédica en Red en el Área de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), and Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain
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  • José C. Fernández-Checa,

    Corresponding author
    1. Liver Unit, and Centro de Investigaciones Biomédicas Esther Koplowitz, Hospital Clínic and Centro de Investigación Biomédica en Red en el Área de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), and Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain
    • Liver Unit, Hospital Clinic, C/Villarroel 170, 08036-Barcelona, Spain
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    • These authors share senior authorship.

  • Montserrat Marí

    Corresponding author
    1. Liver Unit, and Centro de Investigaciones Biomédicas Esther Koplowitz, Hospital Clínic and Centro de Investigación Biomédica en Red en el Área de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), and Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain
    • Liver Unit, Hospital Clinic, C/Villarroel 170, 08036-Barcelona, Spain
    Search for more papers by this author
    • These authors share senior authorship.

    • fax: (34) 93-4515272


  • Potential conflict of interest: Nothing to report.

Abstract

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 α-smooth muscle actin and transforming growth factor-β 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 CCl4 administration, CtsB expression increased in HSCs but not in hepatocytes, and its inactivation mitigated CCl4-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. (HEPATOLOGY 2009.)

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