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

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 expres...

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Bibliographic Details
Published in:Hepatology (Baltimore, Md.) Md.), 2009-04, Vol.49 (4), p.1297-1307
Main Authors: Moles, Anna, Tarrats, Núria, Fernández‐Checa, José C., Marí, Montserrat
Format: Article
Language:English
Subjects:
Actins - metabolism
Animals
Biological and medical sciences
Carbon Tetrachloride
Cathepsin B - physiology
Cathepsin D - physiology
Cell Line
Cell Proliferation
Cell Transdifferentiation
Down-Regulation
Gastroenterology. Liver. Pancreas. Abdomen
Gene Expression
Gene Silencing
Hepatic Stellate Cells - physiology
Humans
Liver Cirrhosis - chemically induced
Liver Cirrhosis - metabolism
Liver Cirrhosis - physiopathology
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Medical sciences
Mice
Mice, Inbred C57BL
Phosphatidylinositol 3-Kinases - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Transforming Growth Factor beta - metabolism
Up-Regulation
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Summary: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.)
ISSN:0270-9139
1527-3350
DOI:10.1002/hep.22753