Skip to main content
SpringerLink
Log in

Osteopontin as a Biomarker in Liver Disease

  • Reference work entry
  • First Online:
Biomarkers in Liver Disease

Abstract

Osteopontin (OPN) is a multifunctional protein, physiologically expressed in the kidney and bone. OPN expression has been attributed to many pathological conditions including inflammation, angiogenesis, fibrosis, and carcinogenesis. OPN was found to contribute to the migration of macrophages into necrotic areas in liver tissue and to serve as a key cytokine within the extracellular matrix in the liver, contributing to fibrogenesis. OPN is also involved in the evolution and progression of various cancers, including hepatocellular carcinoma. Plasma OPN levels were found to predict liver fibrosis in various chronic liver diseases such as nonalcoholic steatohepatitis, alcoholic liver disease, and chronic viral hepatitis. OPN levels correlate significantly with the degree of fibrosis and could serve as a noninvasive biomarker of portal hypertension and as a prognostic parameter in cirrhosis.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 449.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 549.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ALT:

Alaninaminotransferase

AST:

Aspartataminotransferase

HCC:

Hepatocellular carcinoma

HMGB1:

High-mobility group box-1

HSC:

Hepatic stellate cell

HVPG:

Hepatic venous pressure gradient

iNOS:

Inducible nitric oxide synthase

NASH:

Nonalcoholic steatohepatitis

NO:

Nitric oxide

OPN:

Osteopontin

References

  • Apte UM, Banerjee A, McRee R, Wellberg E, Ramaiah SK. Role of osteopontin in hepatic neutrophil infiltration during alcoholic steatohepatitis. Toxicol Appl Pharmacol. 2005;207(1):25–38.

    Article  CAS  PubMed  Google Scholar 

  • Arriazu, E, Ge X, Leung TM, Magdaleno F, Lopategi A, Lu Y, Kitamura N, Urtasun R, Theise N, Antoine DJ, Nieto N. Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury. Gut. 2016 Jan 27, Epub ahead of print.

    Google Scholar 

  • Ashkar S, Weber GF, Panoutsakopoulou V, Sanchirico ME, Jansson M, Zawaideh S, Rittling SR, Denhardt DT, Glimcher MJ, Cantor H. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science. 2000;287(5454):860–4.

    Article  CAS  PubMed  Google Scholar 

  • Bertola A, Deveaux V, Bonnafous S, Rousseau D, Anty R, Wakkach A, Dahman M, Tordjman J, Clement K, McQuaid SE, Frayn KN, Huet PM, Gugenheim J, Lotersztajn S, Le Marchand-Brustel Y, Tran A, Gual P. Elevated expression of osteopontin may be related to adipose tissue macrophage accumulation and liver steatosis in morbid obesity. Diabetes. 2009;58(1):125–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bruha R, Jachymova M, Petrtyl J, Dvorak K, Lenicek M, Urbanek P, Svestka T, Vitek L. Osteopontin: a non-invasive parameter of portal hypertension and prognostic marker of cirrhosis. World J Gastroenterol. 2016;22(12):3441–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Coombes JD, Swiderska-Syn M, Dolle L, Reid D, Eksteen B, Claridge L, Briones-Orta MA, Shetty S, Oo YH, Riva A, Chokshi S, Papa S, Mi Z, Kuo PC, Williams R, Canbay A, Adams DH, Diehl AM, van Grunsven LA, Choi SS, Syn WK. Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice. Gut. 2015;64(7):1120–31.

    Article  CAS  PubMed  Google Scholar 

  • D’Alfonso S, Barizzone N, Giordano M, Chiocchetti A, Magnani C, Castelli L, Indelicato M, Giacopelli F, Marchini M, Scorza R, Danieli MG, Cappelli M, Migliaresi S, Bigliardo B, Sabbadini MG, Baldissera E, Galeazzi M, Sebastiani GD, Minisola G, Ravazzolo R, Dianzani U, Momigliano-Richiardi P. Two single-nucleotide polymorphisms in the 5′ and 3′ ends of the osteopontin gene contribute to susceptibility to systemic lupus erythematosus. Arthritis Rheum. 2005;52(2):539–47.

    Article  PubMed  Google Scholar 

  • Da Silva AP, Pollett A, Rittling SR, Denhardt DT, Sodek J, Zohar R. Exacerbated tissue destruction in DSS-induced acute colitis of OPN-null mice is associated with downregulation of TNF-alpha expression and non-programmed cell death. J Cell Physiol. 2006;208(3):629–39.

    Article  PubMed  Google Scholar 

  • Fisher LW, Torchia DA, Fohr B, Young MF, Fedarko NS. Flexible structures of SIBLING proteins, bone sialoprotein, and osteopontin. Biochem Biophys Res Commun. 2001;280(2):460–5.

    Article  CAS  PubMed  Google Scholar 

  • Franzen A, Heinegard D. Isolation and characterization of two sialoproteins present only in bone calcified matrix. Biochem J. 1985;232(3):715–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ge X, Leung TM, Arriazu E, Lu Y, Urtasun R, Christensen B, Fiel MI, Mochida S, Sorensen ES, Nieto N. Osteopontin binding to lipopolysaccharide lowers tumor necrosis factor-alpha and prevents early alcohol-induced liver injury in mice. Hepatology. 2014;59(4):1600–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gotoh M, Sakamoto M, Kanetaka K, Chuuma M, Hirohashi S. Overexpression of osteopontin in hepatocellular carcinoma. Pathol Int. 2002;52(1):19–24.

    Article  CAS  PubMed  Google Scholar 

  • Hedtjarn M, Mallard C, Hagberg H. Inflammatory gene profiling in the developing mouse brain after hypoxia-ischemia. J Cereb Blood Flow Metab. 2004;24(12):1333–51.

    Article  PubMed  Google Scholar 

  • Huang W, Zhu G, Huang M, Lou G, Liu Y, Wang S. Plasma osteopontin concentration correlates with the severity of hepatic fibrosis and inflammation in HCV-infected subjects. Clin Chim Acta. 2010;411(9–10):675–8.

    Article  CAS  PubMed  Google Scholar 

  • Husain-Krautter S, Kramer JM, Li W, Guo B, Rothstein TL. The osteopontin transgenic mouse is a new model for Sjogren’s syndrome. Clin Immunol. 2015;157(1):30–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hwang SM, Lopez CA, Heck DE, Gardner CR, Laskin DL, Laskin JD, Denhardt DT. Osteopontin inhibits induction of nitric oxide synthase gene expression by inflammatory mediators in mouse kidney epithelial cells. J Biol Chem. 1994;269(1):711–5.

    CAS  PubMed  Google Scholar 

  • Isoda K, Kamezawa Y, Ayaori M, Kusuhara M, Tada N, Ohsuzu F. Osteopontin transgenic mice fed a high-cholesterol diet develop early fatty-streak lesions. Circulation. 2003;107(5):679–81.

    Article  CAS  PubMed  Google Scholar 

  • Karamizadeh Z, Kamali Sarvestani E, Saki F, Karamifar H, Amirhakimi GH, Namavar Shooshtarian MH, Ashkani-Esfahani S. Investigation of osteopontin levels and genomic variation of osteopontin and its receptors in type 1 diabetes mellitus. J Endocrinol Invest. 2013;36(11):1090–3.

    CAS  PubMed  Google Scholar 

  • Kawashima R, Mochida S, Matsui A, YouLuTu ZY, Ishikawa K, Toshima K, Yamanobe F, Inao M, Ikeda H, Ohno A, Nagoshi S, Uede T, Fujiwara K. Expression of osteopontin in Kupffer cells and hepatic macrophages and Stellate cells in rat liver after carbon tetrachloride intoxication: a possible factor for macrophage migration into hepatic necrotic areas. Biochem Biophys Res Commun. 1999;256(3):527–31.

    Article  CAS  PubMed  Google Scholar 

  • Kazanecki CC, Uzwiak DJ, Denhardt DT. Control of osteopontin signaling and function by post-translational phosphorylation and protein folding. J Cell Biochem. 2007;102(4):912–24.

    Article  CAS  PubMed  Google Scholar 

  • Leung TM, Wang X, Kitamura N, Fiel MI, Nieto N. Osteopontin delays resolution of liver fibrosis. Lab Invest. 2013;93(10):1082–9.

    Article  CAS  PubMed  Google Scholar 

  • Liaw L, Skinner MP, Raines EW, Ross R, Cheresh DA, Schwartz SM, Giachelli CM. The adhesive and migratory effects of osteopontin are mediated via distinct cell surface integrins. Role of alpha v beta 3 in smooth muscle cell migration to osteopontin in vitro. J Clin Invest. 1995;95(2):713–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsue Y, Tsutsumi M, Hayashi N, Saito T, Tsuchishima M, Toshikuni N, Arisawa T, George J. Serum osteopontin predicts degree of hepatic fibrosis and serves as a biomarker in patients with hepatitis C virus infection. PLoS One. 2015;10(3):e0118744.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mirza M, Shaughnessy E, Hurley JK, Vanpatten KA, Pestano GA, He B, Weber GF. Osteopontin-c is a selective marker of breast cancer. Int J Cancer. 2008;122(4):889–97.

    Article  CAS  PubMed  Google Scholar 

  • Morales-Ibanez O, Dominguez M, Ki SH, Marcos M, Chaves JF, Nguyen-Khac E, Houchi H, Affo S, Sancho-Bru P, Altamirano J, Michelena J, Garcia-Pagan JC, Abraldes JG, Arroyo V, Caballeria J, Laso FJ, Gao B, Bataller R. Human and experimental evidence supporting a role for osteopontin in alcoholic hepatitis. Hepatology. 2013;58(5):1742–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nabih MI, Aref WM, Fathy MM. Significance of plasma osteopontin in diagnosis of hepatitis C virus-related hepatocellular carcinoma. Arab J Gastroenterol. 2014;15:103.

    Article  PubMed  Google Scholar 

  • Nagoshi S. Osteopontin: versatile modulator of liver diseases. Hepatol Res. 2014;44(1):22–30.

    Article  CAS  PubMed  Google Scholar 

  • Noiri E, Dickman K, Miller F, Romanov G, Romanov VI, Shaw R, Chambers AF, Rittling SR, Denhardt DT, Goligorsky MS. Reduced tolerance to acute renal ischemia in mice with a targeted disruption of the osteopontin gene. Kidney Int. 1999;56(1):74–82.

    Article  CAS  PubMed  Google Scholar 

  • Oldberg A, Franzen A, Heinegard D. Cloning and sequence analysis of rat bone sialoprotein (osteopontin) cDNA reveals an Arg-Gly-Asp cell-binding sequence. Proc Natl Acad Sci U S A. 1986;83(23):8819–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patouraux S, Bonnafous S, Voican CS, Anty R, Saint-Paul MC, Rosenthal-Allieri MA, Agostini H, Njike M, Barri-Ova N, Naveau S, Le Marchand-Brustel Y, Veillon P, Cales P, Perlemuter G, Tran A, Gual P. The osteopontin level in liver, adipose tissue and serum is correlated with fibrosis in patients with alcoholic liver disease. PLoS One. 2012;7(4):e35612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patouraux S, Rousseau D, Rubio A, Bonnafous S, Lavallard VJ, Lauron J, Saint-Paul MC, Bailly-Maitre B, Tran A, Crenesse D, Gual P. Osteopontin deficiency aggravates hepatic injury induced by ischemia-reperfusion in mice. Cell Death Dis. 2014;5:e1208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rabenstein M, Hucklenbroich J, Willuweit A, Ladwig A, Fink GR, Schroeter M, Langen KJ, Rueger MA. Osteopontin mediates survival, proliferation and migration of neural stem cells through the chemokine receptor CXCR4. Stem Cell Res Ther. 2015;6:99.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ramaiah SK, Rittling S. Pathophysiological role of osteopontin in hepatic inflammation, toxicity, and cancer. Toxicol Sci. 2008;103(1):4–13.

    Article  CAS  PubMed  Google Scholar 

  • Rittling SR, Denhardt DT. Osteopontin function in pathology: lessons from osteopontin-deficient mice. Exp Nephrol. 1999;7(2):103–13.

    Article  CAS  PubMed  Google Scholar 

  • Rogers SA, Padanilam BJ, Hruska KA, Giachelli CM, Hammerman MR. Metanephric osteopontin regulates nephrogenesis in vitro. Am J Physiol. 1997;272(4 Pt 2):F469–76.

    CAS  PubMed  Google Scholar 

  • Senger DR, Wirth DF, Hynes RO. Transformed mammalian cells secrete specific proteins and phosphoproteins. Cell. 1979;16(4):885–93.

    Article  CAS  PubMed  Google Scholar 

  • Shang S, Plymoth A, Ge S, Feng Z, Rosen HR, Sangrajrang S, Hainaut P, Marrero JA, Beretta L. Identification of osteopontin as a novel marker for early hepatocellular carcinoma. Hepatology. 2012;55(2):483–90.

    Article  CAS  PubMed  Google Scholar 

  • Simao A, Madaleno J, Silva N, Rodrigues F, Caseiro P, Costa JN, Carvalho A. Plasma osteopontin is a biomarker for the severity of alcoholic liver cirrhosis, not for hepatocellular carcinoma screening. BMC Gastroenterol. 2015;15:73.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sodek J, Ganss B, McKee MD. Osteopontin. Crit Rev Oral Biol Med. 2000;11(3):279–303.

    Article  CAS  PubMed  Google Scholar 

  • Sorensen ES, Petersen TE. Identification of two phosphorylation motifs in bovine osteopontin. Biochem Biophys Res Commun. 1994;198(1):200–5.

    Article  CAS  PubMed  Google Scholar 

  • Sorensen ES, Hojrup P, Petersen TE. Posttranslational modifications of bovine osteopontin: identification of twenty-eight phosphorylation and three O-glycosylation sites. Protein Sci. 1995;4(10):2040–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun J, Xu HM, Zhou HJ, Dong QZ, Zhao Y, Fu LY, Hei ZY, Ye QH, Ren N, Jia HL, Qin LX. The prognostic significance of preoperative plasma levels of osteopontin in patients with TNM stage-I of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2010;136(1):1–7.

    Article  CAS  PubMed  Google Scholar 

  • Syn WK, Oo YH, Pereira TA, Karaca GF, Jung Y, Omenetti A, Witek RP, Choi SS, Guy CD, Fearing CM, Teaberry V, Pereira FE, Adams DH, Diehl AM. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology. 2010;51(6):1998–2007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Syn WK, Choi SS, Liaskou E, Karaca GF, Agboola KM, Oo YH, Mi Z, Pereira TA, Zdanowicz M, Malladi P, Chen Y, Moylan C, Jung Y, Bhattacharya SD, Teaberry V, Omenetti A, Abdelmalek MF, Guy CD, Adams DH, Kuo PC, Michelotti GA, Whitington PF, Diehl AM. Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology. 2011;53(1):106–15.

    Article  CAS  PubMed  Google Scholar 

  • Syn WK, Agboola KM, Swiderska M, Michelotti GA, Liaskou E, Pang H, Xie G, Philips G, Chan IS, Karaca GF, Pereira Tde A, Chen Y, Mi Z, Kuo PC, Choi SS, Guy CD, Abdelmalek MF, Diehl AM. NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut. 2012;61(9):1323–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Terashi T, Aishima S, Taguchi K, Asayama Y, Sugimachi K, Matsuura S, Shimada M, Maehara S, Maehara Y, Tsuneyoshi M. Decreased expression of osteopontin is related to tumor aggressiveness and clinical outcome of intrahepatic cholangiocarcinoma. Liver Int. 2004;24(1):38–45.

    Article  CAS  PubMed  Google Scholar 

  • Uede T. Osteopontin, intrinsic tissue regulator of intractable inflammatory diseases. Pathol Int. 2011;61(5):265–80.

    Article  CAS  PubMed  Google Scholar 

  • Urtasun R, Lopategi A, George J, Leung TM, Lu Y, Wang X, Ge X, Fiel MI, Nieto N. Osteopontin, an oxidant stress sensitive cytokine, up-regulates collagen-I via integrin alpha(V)beta(3) engagement and PI3K/pAkt/NFkappaB signaling. Hepatology. 2012;55(2):594–608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wai PY, Kuo PC. The role of osteopontin in tumor metastasis. J Surg Res. 2004;121(2):228–41.

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Chen B, Shen D, Xue S. Osteopontin protects against cardiac ischemia-reperfusion injury through late preconditioning. Heart Vessels. 2009;24(2):116–23.

    Article  PubMed  Google Scholar 

  • Weber GF, Ashkar S, Glimcher MJ, Cantor H. Receptor-ligand interaction between CD44 and osteopontin (Eta-1). Science. 1996;271(5248):509–12.

    Article  CAS  PubMed  Google Scholar 

  • Young MF, Kerr JM, Termine JD, Wewer UM, Wang MG, McBride OW, Fisher LW. cDNA cloning, mRNA distribution and heterogeneity, chromosomal location, and RFLP analysis of human osteopontin (OPN). Genomics. 1990;7(4):491–502.

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Ye QH, Ren N, Zhao L, Wang YF, Wu X, Sun HC, Wang L, Zhang BH, Liu YK, Tang ZY, Qin LX. The prognostic significance of preoperative plasma levels of osteopontin in patients with hepatocellular carcinoma. J Cancer Res Clin Oncol. 2006;132(11):709–17.

    Article  CAS  PubMed  Google Scholar 

  • Zhao L, Li T, Wang Y, Pan Y, Ning H, Hui X, Xie H, Wang J, Han Y, Liu Z, Fan D. Elevated plasma osteopontin level is predictive of cirrhosis in patients with hepatitis B infection. Int J Clin Pract. 2008;62(7):1056–62.

    Article  CAS  PubMed  Google Scholar 

  • Zohar R, Lee W, Arora P, Cheifetz S, McCulloch C, Sodek J. Single cell analysis of intracellular osteopontin in osteogenic cultures of fetal rat calvarial cells. J Cell Physiol. 1997;170(1):88–100.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Supported by Charles University in Prague (http://www.cuni.cz/UKEN-1.html), No. SVV 260156/2015 and by the Czech Ministry of Health (http://mzcr.cz), No. MZCR-RVO VFN64165.

Author information

Authors and Affiliations

  1. General University Hospital, Charles University in Prague, U Nemocnice 2, 128 08, Prague 2, Czech Republic

    Radan Bruha

Authors
  1. Radan Bruha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Radan Bruha .

Editor information

Editors and Affiliations

  1. Department of Biomedical Science, Faculty of Science and Technology, University of Westminster, London, United Kingdom

    Vinood B. Patel

  2. Diabetes and Nutritional Sciences Research Division, Faculty of Life Science and Medicine, King’s College London, London, United Kingdom

    Victor R. Preedy

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media Dordrecht

About this entry

Cite this entry

Bruha, R. (2017). Osteopontin as a Biomarker in Liver Disease. In: Patel, V., Preedy, V. (eds) Biomarkers in Liver Disease. Biomarkers in Disease: Methods, Discoveries and Applications. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7675-3_44

Download citation

Publish with us

Policies and ethics

Search

Navigation