OPN (osteopontin)) is a Hh (Hedgehog)-regulated cytokine that is up-regulated during chronic liver injury and directly promotes fibrosis. We have reported that Hh signalling enhances viral permissiveness and replication in HCV (hepatitis C virus)-infected cells. Hence we hypothesized that OPN directly promotes HCV replication, and that targeting OPN could be beneficial in HCV. In the present study, we compared the expression of OPN mRNA and protein in HCV (JFH1)-infected Huh7 and Huh7.5 cells, and evaluated whether modulating OPN levels using exogenous OPN ligands (up-regulate OPN) or OPN-specific RNA-aptamers (neutralize OPN) leads to changes in HCV expression. Sera and livers from patients with chronic HCV were analysed to determine whether OPN levels were associated with disease severity or response to therapy. Compared with Huh7 cells, Huh7.5 cells support higher levels of HCV replication (15-fold) and expressed significantly more OPN mRNA (30-fold) and protein. Treating Huh7 cells with OPN ligands led to a dose-related increase in HCV (15-fold) and OPN (8-fold) mRNA. Conversely, treating Huh7.5 cells with OPN-specific RNA aptamers inhibited HCV RNA and protein by >50% and repressed OPN mRNA to basal levels. Liver OPN expression was significantly higher (3-fold) in patients with advanced fibrosis. Serum OPN positively correlated with fibrosis-stage (P=0.009), but negatively correlated with ETBCR (end-of-treatment biochemical response), ETVR (end-of-treatment virological response), SBCR (sustained biochemical response) and SVR (sustained virological response) (P=0.007). The OPN fibrosis score (serum OPN and presence of fibrosis ≥F2) may be a predictor of SVR. In conclusion, OPN is up-regulated in the liver and serum of patients with chronic hepatitis C, and supports increased viral replication. OPN neutralization may be a novel therapeutic strategy in chronic hepatitis C.
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Research Article|
February 26 2014
Osteopontin is up-regulated in chronic hepatitis C and is associated with cellular permissiveness for hepatitis C virus replication
Steve S. Choi;
Steve S. Choi
*Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A.
†Section of Gastroenterology, Durham Veterans Affairs Medical Center, Durham, NC 27705, U.S.A.
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Lee C. Claridge;
Lee C. Claridge
‡Liver Unit, St James's University Hospital, Leeds LS9 7TF, U.K.
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Ravi Jhaveri;
Ravi Jhaveri
§Division of Allergy, Immunology, Rheumatology and Infectious Diseases, Department of Pediatrics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, U.S.A.
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Marzena Swiderska-Syn;
Marzena Swiderska-Syn
*Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A.
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Paul Clark;
Paul Clark
*Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A.
∥Duke Clinical Research Institute, Duke University Medical Center, Durham, NC 27705, U.S.A.
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Ayako Suzuki;
Ayako Suzuki
*Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A.
¶Division of Gastroenterology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, U.S.A.
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Thiago A. Pereira;
Thiago A. Pereira
**Laboratório de Patologia Experimental, Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, BA 40296-710, Brazil
††Núcleo de Doenças Infecciosas, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES, 29040-091, Brazil
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Zhiyong Mi;
Zhiyong Mi
‡‡Department of Surgery, Loyola University Chicago, Maywood, IL 60153, U.S.A.
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Paul C. Kuo;
Paul C. Kuo
‡‡Department of Surgery, Loyola University Chicago, Maywood, IL 60153, U.S.A.
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Cynthia D. Guy;
Cynthia D. Guy
§§Department of Pathology, Duke University Medical Center, Durham, NC 27710, U.S.A.
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Fausto E. L. Pereira;
Fausto E. L. Pereira
††Núcleo de Doenças Infecciosas, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES, 29040-091, Brazil
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Anna Mae Diehl;
Anna Mae Diehl
*Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A.
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Keyur Patel;
Keyur Patel
*Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A.
∥Duke Clinical Research Institute, Duke University Medical Center, Durham, NC 27705, U.S.A.
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Wing-Kin Syn
*Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A.
∥∥Regeneration and Repair, Institute of Hepatology, London, WC1E 6HX, U.K.
¶¶Department of Hepatology, Barts Health NHS Trust, London EC1A 7BE, U.K.
***Department of Biochemistry, University of the Basque Country, Bilbao 48080, Spain
Correspondence: Dr Wing-Kin Syn (email [email protected]).
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Publisher: Portland Press Ltd
Received:
August 13 2013
Revision Received:
November 29 2013
Accepted:
January 20 2014
Accepted Manuscript online:
January 20 2014
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2014 Biochemical Society
2014
Clin Sci (Lond) (2014) 126 (12): 845–855.
Article history
Received:
August 13 2013
Revision Received:
November 29 2013
Accepted:
January 20 2014
Accepted Manuscript online:
January 20 2014
Citation
Steve S. Choi, Lee C. Claridge, Ravi Jhaveri, Marzena Swiderska-Syn, Paul Clark, Ayako Suzuki, Thiago A. Pereira, Zhiyong Mi, Paul C. Kuo, Cynthia D. Guy, Fausto E. L. Pereira, Anna Mae Diehl, Keyur Patel, Wing-Kin Syn; Osteopontin is up-regulated in chronic hepatitis C and is associated with cellular permissiveness for hepatitis C virus replication. Clin Sci (Lond) 1 June 2014; 126 (12): 845–855. doi: https://doi.org/10.1042/CS20130473
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