title: S100A4 promotes liver fibrosis via activation of hepatic stellate cells.
abstract: OBJECTIVE
  S100A4 has been linked to the fibrosis of several organs due to its role as a fibroblast-specific marker. However, the role of S100A4 itself in the development of fibrosis has not been much investigated. Here, we determined whether S100A4 regulates liver fibrogenesis and examined its mechanism by focusing on the activation of hepatic stellate cells (HSCs).
  
  
  METHODS
  S100A4 deficient mice were used to determine the role of S100A4 in liver fibrogenesis. The effect of S100A4 on HSC activation was estimated by using primary mouse HSCs and the human HSC cell line LX-2. Serum levels of S100A4 in cirrhotic patients were determined by ELISA.
  
  
  RESULTS
  S100A4 was found to be secreted by a subpopulation of macrophages and to promote the development of liver fibrosis. It accumulated in the liver during the progression of liver fibrosis and activated HSCs in mice. In vitro studies demonstrated that S100A4 induced the overexpression of alpha-smooth muscle actin through c-Myb in HSCs. Both, the selective depletion of S100A4-expressing cells and knockdown of S100A4 in the liver by RNA interference, resulted in a reduction of liver fibrosis following injury. Importantly, increased S100A4 levels in both the liver tissue and serum correlated positively with liver fibrosis in humans.
  
  
  CONCLUSIONS
  S100A4 promotes liver fibrosis by activating HSCs, which may represent a potential target for anti-fibrotic therapies.
authors.affiliation: Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.affiliation: Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Chengliang
authors.initials: C
authors.lastname: Dai
authors.affiliation: Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xiaoman
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Xinxiang Medical University, Xinxiang, China.
authors.forename: Zhitao
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Guo
authors.affiliation: Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Beijing YouAn Hospital, Capital Medical University, Beijing, China.
authors.forename: Shichun
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Infectious Diseases, Beijing 302 Hospital, Beijing, China.
authors.forename: Fusheng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China.
authors.forename: Henghui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China.
authors.forename: Hongsong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Beijing Key Laboratory of Gene Resource and Molecular Development, Laboratory of Neuroscience and Brain Development, Beijing Normal University, Beijing, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Fan
authors.affiliation: Key Laboratory for Infection and Immunity, Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Shengdian
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. Electronic address: zhihai@ibp.ac.cn.
authors.forename: Zhihai
authors.initials: Z
authors.lastname: Qin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D004247:DNA
keywords: Activation; Hepatic stellate cells; Liver fibrosis; S100A4