Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury

Elena Arriazu, Xiaodong Ge, Tung-Ming Leung, Fernando Magdaleno, Aritz Lopategi, Yongke Lu, Naoto Kitamura, Raquel Urtasun, Neil Theise, Daniel J Antoine, Natalia Nieto

Research output: Contribution to journalArticlepeer-review


OBJECTIVE: Liver fibrosis is associated with significant collagen-I deposition largely produced by activated hepatic stellate cells (HSCs); yet, the link between hepatocyte damage and the HSC profibrogenic response remains unclear. Here we show significant induction of osteopontin (OPN) and high-mobility group box-1 (HMGB1) in liver fibrosis. Since OPN was identified as upstream of HMGB1, we hypothesised that OPN could participate in the pathogenesis of liver fibrosis by increasing HMGB1 to upregulate collagen-I expression.

DESIGN AND RESULTS: Patients with long-term hepatitis C virus (HCV) progressing in disease stage displayed enhanced hepatic OPN and HMGB1 immunostaining, which correlated with fibrosis stage, whereas it remained similar in non-progressors. Hepatocyte cytoplasmic OPN and HMGB1 expression was significant while loss of nuclear HMGB1 occurred in patients with HCV-induced fibrosis compared with healthy explants. Well-established liver fibrosis along with marked induction of HMGB1 occurred in CCl4-injected OpnHep transgenic yet it was less in wild type and almost absent in Opn-/- mice. Hmgb1 ablation in hepatocytes (Hmgb1ΔHep) protected mice from CCl4-induced liver fibrosis. Coculture with hepatocytes that secrete OPN plus HMGB1 and challenge with recombinant OPN (rOPN) or HMGB1 (rHMGB1) enhanced collagen-I expression in HSCs, which was blunted by neutralising antibodies (Abs) and by Opn or Hmgb1 ablation. rOPN induced acetylation of HMGB1 in HSCs due to increased NADPH oxidase activity and the associated decrease in histone deacetylases 1/2 leading to upregulation of collagen-I. Last, rHMGB1 signalled via receptor for advanced glycation end-products and activated the PI3K-pAkt1/2/3 pathway to upregulate collagen-I.

CONCLUSIONS: During liver fibrosis, the increase in OPN induces HMGB1, which acts as a downstream alarmin driving collagen-I synthesis in HSCs.

Original languageEnglish
Pages (from-to)1123-1137
Number of pages15
Issue number6
Early online date12 May 2017
Publication statusE-pub ahead of print - 12 May 2017


  • Acetylation
  • Animals
  • Antibodies, Neutralizing
  • Carbon Tetrachloride
  • Case-Control Studies
  • Cell Nucleus
  • Cells, Cultured
  • Collagen Type I
  • Cytoplasm
  • Disease Progression
  • Gene Expression
  • HMGB1 Protein
  • Hepatic Stellate Cells
  • Hepatitis C, Chronic
  • Hepatocytes
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Humans
  • Liver Cirrhosis
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • NADPH Oxidases
  • Osteopontin
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • Receptor for Advanced Glycation End Products
  • Recombinant Proteins
  • Signal Transduction
  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural


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