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  • Open Access

Osteopontin is a novel downstream target of SOX9 with diagnostic implications for progression of liver fibrosis in humans

Authors

  • James Pritchett,

    1. Endocrinology and Diabetes Group, School of Biomedicine, University of Manchester, Manchester, United Kingdom
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    • These authors contributed equally to this article.

  • Emma Harvey,

    1. Endocrinology and Diabetes Group, School of Biomedicine, University of Manchester, Manchester, United Kingdom
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    • These authors contributed equally to this article.

  • Varinder Athwal,

    1. Endocrinology and Diabetes Group, School of Biomedicine, University of Manchester, Manchester, United Kingdom
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    • These authors contributed equally to this article.

  • Andrew Berry,

    1. Endocrinology and Diabetes Group, School of Biomedicine, University of Manchester, Manchester, United Kingdom
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  • Cliff Rowe,

    1. Endocrinology and Diabetes Group, School of Biomedicine, University of Manchester, Manchester, United Kingdom
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  • Fiona Oakley,

    1. Liver Research Group, Institute of Cellular Medicine, University of Newcastle, Newcastle-upon-Tyne, United Kingdom
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  • Anna Moles,

    1. Liver Research Group, Institute of Cellular Medicine, University of Newcastle, Newcastle-upon-Tyne, United Kingdom
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  • Derek A. Mann,

    1. Liver Research Group, Institute of Cellular Medicine, University of Newcastle, Newcastle-upon-Tyne, United Kingdom
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  • Nicoletta Bobola,

    1. School of Dentistry, University of Manchester, Manchester, United Kingdom
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  • Andrew D. Sharrocks,

    1. Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom
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  • Brian J. Thomson,

    1. School of Molecular Medical Sciences, Nottingham Digestive Diseases Center, Biomedical Research Unit in Gastroenterology and Liver Disease, University of Nottingham and Nottingham University Hospitals, Queens Medical Center Campus, Nottingham United Kingdom
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  • Abed M. Zaitoun,

    1. Department of Cellular Pathology, Nottingham Digestive Diseases Center, Biomedical Research Unit in Gastroenterology and Liver Disease, University of Nottingham and Nottingham University Hospitals, Queens Medical Center Campus, Nottingham United Kingdom
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  • William L. Irving,

    1. School of Molecular Medical Sciences, Nottingham Digestive Diseases Center, Biomedical Research Unit in Gastroenterology and Liver Disease, University of Nottingham and Nottingham University Hospitals, Queens Medical Center Campus, Nottingham United Kingdom
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  • Indra N. Guha,

    1. Liver Unit, National Institute of Health Research, Nottingham Digestive Diseases Center, Biomedical Research Unit in Gastroenterology and Liver Disease, University of Nottingham and Nottingham University Hospitals, Queens Medical Center Campus, Nottingham United Kingdom
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  • Neil A. Hanley,

    1. Endocrinology and Diabetes Group, School of Biomedicine, University of Manchester, Manchester, United Kingdom
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  • Karen Piper Hanley

    Corresponding author
    1. Endocrinology and Diabetes Group, School of Biomedicine, University of Manchester, Manchester, United Kingdom
    • School of Biomedicine, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK===

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    • fax: +44 (0)161 2755958


  • Potential conflict of interest: Nothing to report.

Abstract

Osteopontin (OPN) is an important component of the extracellular matrix (ECM), which promotes liver fibrosis and has been described as a biomarker for its severity. Previously, we have demonstrated that Sex-determining region Y-box 9 (SOX9) is ectopically expressed during activation of hepatic stellate cells (HSC) when it is responsible for the production of type 1 collagen, which causes scar formation in liver fibrosis. Here, we demonstrate that SOX9 regulates OPN. During normal development and in the mature liver, SOX9 and OPN are coexpressed in the biliary duct. In rodent and human models of fibrosis, both proteins were increased and colocalized to fibrotic regions in vivo and in culture-activated HSCs. SOX9 bound a conserved upstream region of the OPN gene, and abrogation of Sox9 in HSCs significantly decreased OPN production. Hedgehog (Hh) signaling has previously been shown to regulate OPN expression directly by glioblastoma (GLI) 1. Our data indicate that in models of liver fibrosis, Hh signaling more likely acts through SOX9 to modulate OPN. In contrast to Gli2 and Gli3, Gli1 is sparse in HSCs and is not increased upon activation. Furthermore, reduction of GLI2, but not GLI3, decreased the expression of both SOX9 and OPN, whereas overexpressing SOX9 or constitutively active GLI2 could rescue the antagonistic effects of cyclopamine on OPN expression. Conclusion: These data reinforce SOX9, downstream of Hh signaling, as a core factor mediating the expression of ECM components involved in liver fibrosis. Understanding the role and regulation of SOX9 during liver fibrosis will provide insight into its potential modulation as an antifibrotic therapy or as a means of identifying potential ECM targets, similar to OPN, as biomarkers of fibrosis. (HEPATOLOGY 2012;56:1108–1116)

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