SOX9 regulated matrix proteins are increased in patients serum and correlate with severity of liver fibrosis

Varinder S. Athwal; James Pritchett; Katherine Martin; Jessica Llewellyn; Jennifer Scott; Emma Harvey; Abed M. Zaitoun; Aoibheann F. Mullan; Leo A.H. Zeef; Scott L. Friedman; William L. Irving; Neil A. Hanley; Indra N. Guha; Karen Piper Hanley

doi:10.1038/s41598-018-36037-4

SOX9 regulated matrix proteins are increased in patients serum and correlate with severity of liver fibrosis

Varinder S. Athwal, James Pritchett, Katherine Martin, Jessica Llewellyn, Jennifer Scott, Emma Harvey, Abed M. Zaitoun, Aoibheann F. Mullan, Leo A.H. Zeef, Scott L. Friedman, William L. Irving, Neil A. Hanley, Indra N. Guha, Karen Piper Hanley^*

^*Corresponding author for this work

Medicine and Health

Research output: Contribution to journal › Article › peer-review

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Abstract

Extracellular matrix (ECM) deposition and resultant scar play a major role in the pathogenesis and progression of liver fibrosis. Identifying core regulators of ECM deposition may lead to urgently needed diagnostic and therapetic strategies for the disease. The transcription factor Sex determining region Y box 9 (SOX9) is actively involved in scar formation and its prevalence in patients with liver fibrosis predicts progression. In this study, transcriptomic approaches of Sox9-abrogated myofibroblasts identified >30% of genes regulated by SOX9 relate to the ECM. Further scrutiny of these data identified a panel of highly expressed ECM proteins, including Osteopontin (OPN), Osteoactivin (GPNMB), Fibronectin (FN1), Osteonectin (SPARC) and Vimentin (VIM) as SOX9 targets amenable to assay in patient serum. In vivo all SOX-regulated targets were increased in human disease and mouse models of fibrosis and decreased following Sox9-loss in mice with parenchymal and biliary fibrosis. In patient serum samples, SOX9-regulated ECM proteins were altered in response to fibrosis severity, whereas comparison with established clinical biomarkers demonstrated superiority for OPN and VIM at detecting early stages of fibrosis. These data support SOX9 in the mechanisms underlying fibrosis and highlight SOX9 and its downstream targets as new measures to stratify patients with liver fibrosis.

Original language	English
Article number	17905
Journal	Scientific Reports
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41598-018-36037-4
Publication status	Published - 1 Dec 2018

Bibliographical note

Funding Information:
This work was supported by the Medical Research Council (MRC; KPH, MR/J003352/1 & MR/P023541/1; KM and VSA were funded as MRC Clinical Training Fellows); the Manchester NIHR Biomedical Research Centre and the Wellcome Trust (NAH, WT088566MA). The Core Facilities at the University of Manchester are acknowledged for their technical help and support.

Publisher Copyright:
© 2018, The Author(s).

ASJC Scopus subject areas

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UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41598-018-36037-4

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Athwal, V. S., Pritchett, J., Martin, K., Llewellyn, J., Scott, J., Harvey, E., Zaitoun, A. M., Mullan, A. F., Zeef, L. A. H., Friedman, S. L., Irving, W. L., Hanley, N. A., Guha, I. N., & Hanley, K. P. (2018). SOX9 regulated matrix proteins are increased in patients serum and correlate with severity of liver fibrosis. Scientific Reports, 8(1), Article 17905. https://doi.org/10.1038/s41598-018-36037-4

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title = "SOX9 regulated matrix proteins are increased in patients serum and correlate with severity of liver fibrosis",

abstract = "Extracellular matrix (ECM) deposition and resultant scar play a major role in the pathogenesis and progression of liver fibrosis. Identifying core regulators of ECM deposition may lead to urgently needed diagnostic and therapetic strategies for the disease. The transcription factor Sex determining region Y box 9 (SOX9) is actively involved in scar formation and its prevalence in patients with liver fibrosis predicts progression. In this study, transcriptomic approaches of Sox9-abrogated myofibroblasts identified >30% of genes regulated by SOX9 relate to the ECM. Further scrutiny of these data identified a panel of highly expressed ECM proteins, including Osteopontin (OPN), Osteoactivin (GPNMB), Fibronectin (FN1), Osteonectin (SPARC) and Vimentin (VIM) as SOX9 targets amenable to assay in patient serum. In vivo all SOX-regulated targets were increased in human disease and mouse models of fibrosis and decreased following Sox9-loss in mice with parenchymal and biliary fibrosis. In patient serum samples, SOX9-regulated ECM proteins were altered in response to fibrosis severity, whereas comparison with established clinical biomarkers demonstrated superiority for OPN and VIM at detecting early stages of fibrosis. These data support SOX9 in the mechanisms underlying fibrosis and highlight SOX9 and its downstream targets as new measures to stratify patients with liver fibrosis.",

author = "Athwal, {Varinder S.} and James Pritchett and Katherine Martin and Jessica Llewellyn and Jennifer Scott and Emma Harvey and Zaitoun, {Abed M.} and Mullan, {Aoibheann F.} and Zeef, {Leo A.H.} and Friedman, {Scott L.} and Irving, {William L.} and Hanley, {Neil A.} and Guha, {Indra N.} and Hanley, {Karen Piper}",

note = "Funding Information: This work was supported by the Medical Research Council (MRC; KPH, MR/J003352/1 & MR/P023541/1; KM and VSA were funded as MRC Clinical Training Fellows); the Manchester NIHR Biomedical Research Centre and the Wellcome Trust (NAH, WT088566MA). The Core Facilities at the University of Manchester are acknowledged for their technical help and support. Publisher Copyright: {\textcopyright} 2018, The Author(s).",

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doi = "10.1038/s41598-018-36037-4",

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Athwal, VS, Pritchett, J, Martin, K, Llewellyn, J, Scott, J, Harvey, E, Zaitoun, AM, Mullan, AF, Zeef, LAH, Friedman, SL, Irving, WL, Hanley, NA, Guha, IN & Hanley, KP 2018, 'SOX9 regulated matrix proteins are increased in patients serum and correlate with severity of liver fibrosis', Scientific Reports, vol. 8, no. 1, 17905. https://doi.org/10.1038/s41598-018-36037-4

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AU - Athwal, Varinder S.

AU - Pritchett, James

AU - Martin, Katherine

AU - Llewellyn, Jessica

AU - Scott, Jennifer

AU - Harvey, Emma

AU - Zaitoun, Abed M.

AU - Mullan, Aoibheann F.

AU - Zeef, Leo A.H.

AU - Friedman, Scott L.

AU - Irving, William L.

AU - Hanley, Neil A.

AU - Guha, Indra N.

AU - Hanley, Karen Piper

N1 - Funding Information: This work was supported by the Medical Research Council (MRC; KPH, MR/J003352/1 & MR/P023541/1; KM and VSA were funded as MRC Clinical Training Fellows); the Manchester NIHR Biomedical Research Centre and the Wellcome Trust (NAH, WT088566MA). The Core Facilities at the University of Manchester are acknowledged for their technical help and support. Publisher Copyright: © 2018, The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Extracellular matrix (ECM) deposition and resultant scar play a major role in the pathogenesis and progression of liver fibrosis. Identifying core regulators of ECM deposition may lead to urgently needed diagnostic and therapetic strategies for the disease. The transcription factor Sex determining region Y box 9 (SOX9) is actively involved in scar formation and its prevalence in patients with liver fibrosis predicts progression. In this study, transcriptomic approaches of Sox9-abrogated myofibroblasts identified >30% of genes regulated by SOX9 relate to the ECM. Further scrutiny of these data identified a panel of highly expressed ECM proteins, including Osteopontin (OPN), Osteoactivin (GPNMB), Fibronectin (FN1), Osteonectin (SPARC) and Vimentin (VIM) as SOX9 targets amenable to assay in patient serum. In vivo all SOX-regulated targets were increased in human disease and mouse models of fibrosis and decreased following Sox9-loss in mice with parenchymal and biliary fibrosis. In patient serum samples, SOX9-regulated ECM proteins were altered in response to fibrosis severity, whereas comparison with established clinical biomarkers demonstrated superiority for OPN and VIM at detecting early stages of fibrosis. These data support SOX9 in the mechanisms underlying fibrosis and highlight SOX9 and its downstream targets as new measures to stratify patients with liver fibrosis.

AB - Extracellular matrix (ECM) deposition and resultant scar play a major role in the pathogenesis and progression of liver fibrosis. Identifying core regulators of ECM deposition may lead to urgently needed diagnostic and therapetic strategies for the disease. The transcription factor Sex determining region Y box 9 (SOX9) is actively involved in scar formation and its prevalence in patients with liver fibrosis predicts progression. In this study, transcriptomic approaches of Sox9-abrogated myofibroblasts identified >30% of genes regulated by SOX9 relate to the ECM. Further scrutiny of these data identified a panel of highly expressed ECM proteins, including Osteopontin (OPN), Osteoactivin (GPNMB), Fibronectin (FN1), Osteonectin (SPARC) and Vimentin (VIM) as SOX9 targets amenable to assay in patient serum. In vivo all SOX-regulated targets were increased in human disease and mouse models of fibrosis and decreased following Sox9-loss in mice with parenchymal and biliary fibrosis. In patient serum samples, SOX9-regulated ECM proteins were altered in response to fibrosis severity, whereas comparison with established clinical biomarkers demonstrated superiority for OPN and VIM at detecting early stages of fibrosis. These data support SOX9 in the mechanisms underlying fibrosis and highlight SOX9 and its downstream targets as new measures to stratify patients with liver fibrosis.

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SOX9 regulated matrix proteins are increased in patients serum and correlate with severity of liver fibrosis

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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