Osteopontin induces ductular reaction contributing to liver fibrosis.
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.
Division of Liver Diseases, Department of Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA.
Xiaodong
X
Wang
Division of Liver Diseases, Department of Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA.
Aritz
A
Lopategi
Division of Liver Diseases, Department of Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA.
Xiaodong
X
Ge
Division of Liver Diseases, Department of Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA.
Yongke
Y
Lu
Division of Liver Diseases, Department of Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA.
Naoto
N
Kitamura
Division of Liver Diseases, Department of Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA.
Raquel
R
Urtasun
Division of Liver Diseases, Department of Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA.
Tung-Ming
TM
Leung
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Maria Isabel
MI
Fiel
Division of Liver Diseases, Department of Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA.
Natalia
N
Nieto
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D018920:Coculture Techniques; D006500:Hepatic Duct, Common / Q000187:drug effects / Q000473:pathology*; D022781:Hepatocytes / Q000502:physiology; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008103:Liver Cirrhosis / Q000473:pathology* / Q000503:physiopathology*; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D053495:Osteopontin / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D019394:Ki-67 Antigen; D016212:Transforming Growth Factor beta; D053495:Osteopontin
Cell Matrix Interaction; Extracellular Matrix; Fibrogenesis; Hepatic Fibrosis; TGF-Beta