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 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.


CONCLUSIONS
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.
Moles
Anna
A
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.
Tarrats
Núria
N
Fernández-Checa
José C
JC
Marí
Montserrat
M
D000199:Actins / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride; D002401:Cathepsin B / Q000502:physiology*; D002402:Cathepsin D / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D054338:Cell Transdifferentiation; D015536:Down-Regulation; D015870:Gene Expression; D020868:Gene Silencing; D055166:Hepatic Stellate Cells / Q000502:physiology*; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation
C558396:Acta2 protein, mouse; D000199:Actins; D016212:Transforming Growth Factor beta; D002251:Carbon Tetrachloride; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D002401:Cathepsin B; C533915:Ctsb protein, mouse; D002402:Cathepsin D; C533923:Ctsd protein, mouse