Digestive Diseases and Sciences

, Volume 57, Issue 6, pp 1430–1431 | Cite as

Osteopontin Biomarker in Inflammatory Bowel Disease, Animal Models and Target for Drug Discovery

  • Manuela G. Neuman

Inflammatory bowel disease (IBD) is an immune-mediated disease caused by abnormal mucosal T-cell response to bacteria in the intestinal lumen. In Crohn’s disease (CD), mucosal T cells exhibit the TH1 phenotype, whereas ulcerative colitis (UC) is believed to have a TH2 phenotype [1].

In the absence of a single test, calculating disease activity in IBD remains a complicated task. An accurate and reliable marker for measuring CD or UC activity for routine clinical practice and in clinical trials has to be based on clinical judgment of histologic and endoscopic imaging. Therefore, validated accurate and objective measures of inflammatory activity in IBD using a reliable, non-invasive biomarker is needed [2]. Proteonome biomarkers are used in the diagnostics of IBD, but they are expensive and not all of them are validated [3].

Several recent reports have suggested an important role for osteopontin (OPN) in the pathogenesis of IBD as well as its possible use as a biomarker [4, 5, 6, 7, 8, 9, 10]. Masuda et al. demonstrated that expression of OPN is significantly elevated in the mucosa of patients with UC [6]. Elevated OPN expression in UC was demonstrated using immunohistochemistry and ultrastructure analysis [7, 8]. In CD, Gassler et al. reported an elevated OPN expression in plasma cells, but not in epithelial cells [9]. Moreover, Sato et al. observed an elevated plasma OPN and significant correlation with disease activity in CD, but not in UC [10].

Osteopontin, a Th1 cytokine, is up-regulated in relation to the severity of the disease [11]. Moreover, since it is an adhesive glycoprotein containing the peptide sequence glycine ± arginine ± aspartate ± serine it promotes cell attachment [12]. Osteopontin and tumor necrosis factor receptor signaling (TNFRS) F14 are genes associated with fibrosis/cell adhesion molecules [1, 13]. Blockade of these cell adhesion molecule interactions prevents the trafficking of leukocytes across the vascular endothelium and, subsequently, into the parenchymal tissue [14, 15, 16]. Alpha-4 integrins bind additional ligands in tissues, including OPN and epitopes of fibronectin. This is the rationale for using the mechanism of monoclonal antibodies in clinical practice. The scope may be to suppress ongoing inflammatory reactions in diseased tissues by inhibition of α4-positive leukocytes with ligands. Inhibiting the existing inflammatory activity at the disease site, along with inhibition of further recruitment of immune cells into inflamed tissue, via interaction with adhesion molecules such as the vascular adhesion molecule will reduce the inflammation and intestinal fibrosis [17, 18, 19].

On the basis of these findings, several researchers described animal models that can mimic the OPN-induced colitis in vivo as well as block OPN-induced inflammation [20, 21, 22, 23].

In this issue is the article “Osteopontin ablation attenuates progression of TNBS-induced colitis model.” In this study, Oz et al. elegantly demonstrate that by ablating the OPN activity the colitis is suppressed [24]. The developmental stages of colonic inflammation in a modified trinitrobenzene sulfonic acid (TNBS) model that mimics Crohn’s disease have been defined as acute, subacute, and chronic. The researchers used OPN deficient mice, with a targeted disruption of the opn gene in a C57BL/6. TNBS-treated wildtype mice developed severe colitis but OPN-deficient mice were significantly protected.

Animal models using OPN-deficient mice have the ability to conclude that OPN plays a role in acute and chronic intestinal inflammation. This will prove to be a fertile area for future research in drug discovery. Animal models mimicking OPN-induced colitis and responses to drugs can also be an attempt to match individual therapies to individual patients. In addition, OPN shows promise as a useful clinical marker of disease activity in IBD and may have a role in the day-to-day management of patients.


  1. 1.
    Neuman MG. Immune dysfunction in inflammatory bowel disease. Trans Res. 2007;149:173–186.CrossRefGoogle Scholar
  2. 2.
    Ullman TA, Palmon R. The certain uncertainty of measuring disease activity in IBD. J Clin Gastroenterol. 2007;41:123–125.PubMedCrossRefGoogle Scholar
  3. 3.
    Meuwis MA, Fillet M, Geurts P, et al. Biomarker discovery for inflammatory bowel disease, using proteomic serum profiling. Biochem Pharmacol. 2007;73:1422–1433.PubMedCrossRefGoogle Scholar
  4. 4.
    Glas J, Seiderer J, Bayrle C, et al. The role of osteopontin (OPN/SPP1) haplotypes in the susceptibility to Crohn’s disease. PLoS ONE. 2011;6:e29309.PubMedCrossRefGoogle Scholar
  5. 5.
    Mishima R, Takeshima F, Sawai T, et al. High plasma osteopontin levels in patients with inflammatory bowel disease. J Clin Gastroenterol. 2007;41:167–172.PubMedCrossRefGoogle Scholar
  6. 6.
    Masuda H, Takahashi Y, Asai S, Hemmi A, Takayama T. Osteopontin expression in ulcerative colitis is distinctly different from that in Crohn’s disease and diverticulitis. J Gastroenterol. 2005;40:409–413.PubMedCrossRefGoogle Scholar
  7. 7.
    Masuda H, Takahashi Y, Asai S, Takayama T. Distinct gene expression of osteopontin in patients with ulcerative colitis. J Surg Res. 2003;111:85–90.PubMedCrossRefGoogle Scholar
  8. 8.
    Hong Q, Dvorak AM. Ultrastructural localization of osteopontin immunoreactivity in phagolysosomes and secretory granules of cells in human intestine. Histochem J. 1997;29:801–812.CrossRefGoogle Scholar
  9. 9.
    Gassler N, Autschbach F, Gauer S, et al. Expression of osteopontin (Eta-1) in Crohn disease of the terminal ileum. Scand J Gastroenterol. 2002;37:1286–1295.PubMedCrossRefGoogle Scholar
  10. 10.
    Sato T, Nakai T, Tamura N, et al. Osteopontin/Eta-1 upregulated in Crohn’s disease regulates the Th1 immune response. Gut. 2005;54:1254–1262.PubMedCrossRefGoogle Scholar
  11. 11.
    Ashkar S, Weber GF, Panoutsakopoulou V, et al. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science. 2000;287:860–864.PubMedCrossRefGoogle Scholar
  12. 12.
    Gordon JN, MacDonald TT. Osteopontin: a new addition to the constellation of cytokines which drive T helper cell type 1 responses in Crohn’s disease. Gut. 2005;54:1213–1215.PubMedCrossRefGoogle Scholar
  13. 13.
    Briskin M, Winsor-Hines D, Shyjan A, et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathology. 1997;151:97–110.Google Scholar
  14. 14.
    Jones SC, Banks RE, Haidar A, et al. Adhesion molecules in inflammatory bowel disease. Gut. 1995;36:724–730.PubMedCrossRefGoogle Scholar
  15. 15.
    Podolsky KD, Lobb R, King N, et al. Attention of colitis in the cotton-top tamarin by anti-α4 integrin monoclonal antibody. J Clin Invest. 1993;92:372–380.PubMedCrossRefGoogle Scholar
  16. 16.
    Hesterberg P, Windsor-Hines D, Briskin M, et al. Rapid resolution of chronic colitis in the cotton-top tamarin with an antibody to a Gut-Homing Integrin α4β7. Gastroenterology. 1996;111:1373–1380.PubMedCrossRefGoogle Scholar
  17. 17.
    Rieder F, Fiocchi C. Intestinal fibrosis in inflammatory bowel disease: progress in basic and clinical science. Curr Opin Gastroenterol. 2008;24:462–468.PubMedCrossRefGoogle Scholar
  18. 18.
    Agnholt J, Kelsen J, Schack L, Hvas CL, Dahlerup JF, Sørensen ES. Osteopontin, a protein with cytokine-like properties, is associated with inflammation in Crohn’s disease. Scand J Immunol. 2007;65:453–460.PubMedCrossRefGoogle Scholar
  19. 19.
    Wine E, Shen-Tu G, Gareau MG, et al. Osteopontin mediates Citrobacter rodentium-induced colonic epithelial cell hyperplasia and attaching-effacing lesions. Am J Pathol. 2010;177:1320–1332.PubMedCrossRefGoogle Scholar
  20. 20.
    Oz HS, Chen TS, Nagasawa H. Comparative efficacies of 2 cysteine prodrugs and a glutathione delivery agent in a colitis model. Trans Res. 2007;150:122–129.CrossRefGoogle Scholar
  21. 21.
    Zhong J, Eckhardt ER, Oz HS, Bruemmer D, de Villiers WJ. Osteopontin deficiency protects mice from Dextran sodium sulfate-induced colitis. Inflamm Bowel Dis. 2006;12:790–796.PubMedCrossRefGoogle Scholar
  22. 22.
    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;208:629–639.PubMedCrossRefGoogle Scholar
  23. 23.
    Fan K, Zhang B, Yang H, et al. A humanized anti-osteopontin antibody protects from Concanavalin A induced-liver injury in mice. Eur J Pharmacol. 2011;657:144–151.PubMedCrossRefGoogle Scholar
  24. 24.
    Oz HS, Zhong J, de Villiers WJS. Osteopontin ablation attenuates progression of colitis in TNBS model. Dig Dis Sci. (Epub ahead of print). doi: 10.1007/s10620-011-2009-z.

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.In Vitro Drug Safety and Biotechnology, Department of Pharmacology and Toxicology, Faculty of Medicine, Institute of Drug ResearchUniversity of TorontoTorontoCanada

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