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Osteopontin induces ductular reaction contributing to liver fibrosis
  1. Xiaodong Wang1,
  2. Aritz Lopategi1,
  3. Xiaodong Ge1,
  4. Yongke Lu1,
  5. Naoto Kitamura1,
  6. Raquel Urtasun1,
  7. Tung-Ming Leung1,
  8. Maria Isabel Fiel2,
  9. Natalia Nieto1
  1. 1Division of Liver Diseases, Department of Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA
  2. 2Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  1. Corresponence to Dr Natalia Nieto, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Box 1123, 1425 Madison Avenue, Room 11-70, New York, NY 10021, USA; natalia.nieto{at}mssm.edu

Abstract

Objective In human chronic liver disease, there is association between ductular reaction (DR) and fibrosis; yet, the mechanism triggering its onset and its role in scar formation remains unknown. Since we previously showed that osteopontin (OPN) is highly induced during drug-induced liver fibrosis, we hypothesised that OPN could drive oval cells (OC) expansion and DR and signal to hepatic stellate cells (HSC) to promote scarring.

Results In vivo studies demonstrated increased OPN expression in biliary epithelial cells (BEC) and in OC in thioacetamide (TAA)-treated mice. OPN ablation protected mice from TAA and bile duct ligation-induced liver injury, DR and scarring. This was associated with greater hepatocyte proliferation, lower OC expansion and DR along with less fibrosis, suggesting that OPN could activate the OC compartment to differentiate into BEC, which could then signal to HSC to enhance scarring. Since TAA-treated wild-type mice and cirrhotic patients showed TGF-β+ BEC, which were lacking in TAA-treated Opn−/− mice and in healthy human explants, this suggested that OPN could regulate TGF-β, a profibrogenic factor. In vitro experiments confirmed that recombinant OPN (rOPN) decreases hepatocyte proliferation and increases OC and BEC proliferation. To evaluate how BEC regulate collagen-I production in HSC, co-cultures were established. Co-cultured BEC upregulated OPN and TGF-β expression and enhanced collagen-I synthesis by HSC. Lastly, recombinant TGF-β (rTGFβ) and rOPN promoted BEC proliferation and neutralisation of OPN and TGF-β reduced collagen-I expression in co-cultured HSC.

Conclusions OPN emerges as a key matricellular protein driving DR and contributing to scarring and liver fibrosis via TGF-β.

  • Cell Matrix Interaction
  • Extracellular Matrix
  • Fibrogenesis
  • Hepatic Fibrosis
  • TGF-Beta

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