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Elevated Serum Osteopontin Levels in Chronic Hepatitis C Virus Infection: Association with Autoimmune Rheumatologic Manifestations

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Abstract

Owing to the suggested role of osteopontin (OPN) in inflammation, autoimmunity and fibrosis, we investigated their serum concentrations in chronic hepatitis C virus (HCV) infected patients with and without autoimmune manifestations and correlated those levels to clinical manifestations and the histological severity of hepatic fibrosis. A total of 70 chronic HCV-infected patients (35 with and 35 without autoimmune rheumatic manifestations‏) were compared with 35 healthy volunteers matched for age and gender. Epidemiological, clinical, immunochemical and virological data were prospectively collected. OPN serum levels were assessed by an Enzyme Linked Immunosorbant Assay. The mean serum OPN levels were higher in HCV patients with autoimmune rheumatologic manifestations and in patients without; than that for the normal controls (p = 0.000). The mean OPN values progressively increased by increasing severity of liver fibrosis (p = 0.009). Multivariate analysis revealed that the presence of rheumatologic manifestations had the highest predictive value (b = 7.141, Beta = 0.414, p = 0.000) followed by liver fibrosis (b = 4.522, Beta = 0.444, p = 0.000) on the variation of OPN levels in our HCV patients. Among the group of patients with HCV and rheumatologic involvement, OPN serum levels were higher in patients with positive cryoglobulin and rheumatoid factor than in those without, and with systemic vasculitis than in those without. Correlation analysis didn’t reveal any statistical significance of OPN with age, serum albumin, aminotransferases and viral load. Our data suggests OPN as a promising marker for HCV associated autoimmune rheumatologic involvement, particularly with regard to development of vasculitis and cryoglobinemia. In addition, it could serve as a biomarker to evaluate the severity of liver damages in HCV infected subjects.

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References

  1. Scatena M, Liaw L, Giachelli CM. Osteopontin. A multifunctional molecule regulating chronic inflammation and vascular disease. Arterioscler Thromb Vasc Biol. 2007;27:2302–9.

    Article  PubMed  CAS  Google Scholar 

  2. Wang KX, Denhardt DT. Osteopontin: role in immune regulation and stress responses. Cytokine Growth Factor Rev. 2008;19(5–6):333–45.

    Article  PubMed  CAS  Google Scholar 

  3. Cho HJ, Cho HJ, Kim HS. Osteopontin: a multifunctional protein at the crossroads of inflammation, atherosclerosis, and vascular calcification. Curr Atheroscler Rep. 2009;11(3):206–13.

    Article  PubMed  CAS  Google Scholar 

  4. Lund SA, Giachelli CM, Scatena M. The role of osteopontin in inflammatory processes. J Cell Commun Signal. 2009;3:311–22.

    Article  PubMed  Google Scholar 

  5. Masutani K, Akahoshi M, Tsuruya K, Tokumoto M, Ninomiya T, Kohsaka T, Fukuda K, Kanai H, Nakashima H, Otsuka T, Hirakata H. Predominance of Th1 immune response in diffuse proliferative lupus nephritis. Arthritis Rheum. 2001;44:2097–106.

    Article  PubMed  CAS  Google Scholar 

  6. Ohshima S, Yamaguchi N, Nishioka K, Mima T, Ishii T, Umeshita-Sasai M, Kobayashi H, Shimizu M, Katada Y, Wakitani S, Murata N, Nomura S, Matsuno H, Katayama R, Kon S, Inobe M, Uede T, Kawase I, Saeki Y. Enhanced local production of osteopontin in rheumatoid joints. J Rheumatol. 2002;29:2061–7.

    PubMed  CAS  Google Scholar 

  7. Lorenzen J, Lovric S, Krämer R, Haller H, Haubitz M. Osteopontin in antineutrophil cytoplasmic autoantibody-associated vasculitis: relation to disease activity, organ manifestation and immunosuppressive therapy. Ann Rheum Dis. 2010;69(6):1169–7.

    Article  PubMed  CAS  Google Scholar 

  8. Steinman L, Martin R, Bernard C, Conlon P, Oksenberg JR. Multiple sclerosis: deeper understanding of its pathogenesis reveals new targets for therapy. Annu Rev Neurosci. 2002;25:491–505.

    Article  PubMed  CAS  Google Scholar 

  9. Lorenzen JM, Krämer R, Meier M, Werfel T, Wichmann K, Hoeper MM, Riemekasten G, Becker MO, Haller H, Witte T. Osteopontin in the development of systemic sclerosis–relation to disease activity and organ manifestation. Rheumatology (Oxford). 2010;49(10):1989–91.

    Article  CAS  Google Scholar 

  10. Erturkler E, Cıcek D, Kaman D, Ozdogan S, Bakar Dertlıoglu S. Plasma osteopontin levels in patients with Behcet's disease and psoriasis. Eur J Dermatol. 2011;21(2):203–8.

    PubMed  Google Scholar 

  11. Medica A, Salobir B, Tercelj M, Peterlin B. Genetic variation in osteopontin gene is associated with susceptibility to sarcoidosis in Slovenian population. Dis Markers. 2009;27(6):295–302.

    PubMed  Google Scholar 

  12. Arai M, Yokosuka O, Kanda T, Fukai K, Imazeki F, Muramatsu M, Seki N, Miyazaki M, Ochiai T, Hirasawa H, Saisho H. Serum osteopontin levels in patients with acute liver dysfunction. Scand J Gastroenterol. 2006;41(1):102–10.

    Article  PubMed  CAS  Google Scholar 

  13. Matsui A, Mochida S, Ohno A, Nagoshi S, Hirose T, Fujiwara K. Plasma osteopontin levels in patients with fulminant hepatitis. Hepatol Res. 2004;29(4):202–6.

    Article  PubMed  CAS  Google Scholar 

  14. 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  PubMed  CAS  Google Scholar 

  15. Bessa SS, Elwan NM, Suliman GA, El-Shourbagy SH. Clinical significance of plasma osteopontin level in Egyptian patients with hepatitis C virus-related hepatocellular carcinoma. Arch Med Res. 2010;41(7):541–7.

    Article  Google Scholar 

  16. Libra M, Indelicato M, De Re V, Zignego AL, Chiocchetti A, Malaponte G, Dianzani U, Nicoletti F, Stivala F, McCubrey JA, Mazzarino MC. Elevated serum levels of osteopontin in HCV-associated lymphoproliferative disorders. Cancer Biol Ther. 2005;4(11):1192–4.

    Article  PubMed  CAS  Google Scholar 

  17. Miller FD, Abu-Raddad LJ. Evidence of intense ongoing endemic transmission of hepatitis C virus in Egypt. PNAS. 2010;107:14757–62.

    Article  PubMed  Google Scholar 

  18. Jimenez-Sousa MA, Almansa R, de la Fuente C, Caro-Paton A, Ruiz L, Sanchez-Antolín G, Gonzalez JM, Aller R, Alcaide N, Largo P, Resino S, de Lejarazu RO, Bermejo-Martin JF. Down-modulation of Th1, Th17 responses after treatment in hepatitis C virus infection. Eur Cytokine Netw. 2010;21(2):84–91.

    PubMed  CAS  Google Scholar 

  19. Jacobson IM, Cacoub P, Dal Maso L, Harrison SA, Younossi ZM. Manifestations of chronic hepatitis C virus infection beyond the liver. Clin Gastroenterol Hepatol. 2010;8(12):1017–29.

    Article  PubMed  Google Scholar 

  20. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR cooperative study group. Hepatol. 1996;24:289–93.

    Article  CAS  Google Scholar 

  21. Okamoto H, Okada S, Sugiyama Y, Tanaka T, Sugai Y, Akahane Y, Machida A, Mishiro S, Yoshizawa H, Miyakawa Y. Detection of hepatitis C virus RNA by a two-stage polymerase chain reaction with two pairs of primers deduced from the 5'-noncoding region. Jpn J Exp Med. 1990;60:215–22.

    PubMed  CAS  Google Scholar 

  22. Mochida S, Yoshimoto T, Mimura S, Inao M, Matsui A, Ohno A, Koh H, Saitoh E, Nagoshi S, Fujiwara K. Transgenic mice expressing osteopontin in hepatocytes as a model of autoimmune hepatitis. Biochem Biophys Res Commun. 2004;317:114–20.

    Article  PubMed  CAS  Google Scholar 

  23. Saitoh E, Matsui A, Inao M, Mimura S, Koh H, Ohno A, Nagoshi S, Kayano H, Yoshimoto T, Mochida S, Fujiwara K. Extrahepatic manifestations in transgenic mice of osteopontin in hepatocytes—A clue to advent of pathological state in various organs of chronic hepatitis C patients. Hepatol Res. 2005;31:197–202.

    Article  PubMed  CAS  Google Scholar 

  24. Anborgh PH, Mutrie JC, Tuck AB, Chambers AF. Role of the metastasis-promoting protein osteopontin in the tumour microenvironment. J Cell Mol Med. 2010;14:2037–44.

    Article  PubMed  CAS  Google Scholar 

  25. Zignego AL. Enhanced TH1 cytokine production in hepatitis C virus-infected patients with mixed cryoglobulinemia: understanding the pathological issue. J Hepatol. 2004;41:1045–9.

    Article  PubMed  CAS  Google Scholar 

  26. Lin YH, Yang-Yen HF. The osteopontin-CD44 survival signal involves activation of the phosphatidylinositol 3-kinase/Akt signaling pathway. J Biol Chem. 2001;276:46024–30.

    Article  PubMed  CAS  Google Scholar 

  27. Suzuki H, Amizuka N, Oda K, Li M, Yoshie H, Ohshima H, Noda M, Maeda T. Histological evidence of the altered distribution of osteocytes and bone matrix synthesis in klotho-deficient mice. Arch Histol Cytol. 2005;68:371–81.

    Article  PubMed  Google Scholar 

  28. Whitington PF, Malladi P, Melin-Aldana H, Azzam R, Mack CL, Sahai A. Expression of osteopontin correlates with portal biliary proliferation and fibrosis in biliary atresia. Pediatr Res. 2005;57:837–44.

    Article  PubMed  CAS  Google Scholar 

  29. 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, Calès 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  PubMed  CAS  Google Scholar 

  30. 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  PubMed  CAS  Google Scholar 

  31. Syn WK, Agboola KM, Swiderska M, Michelotti GA, Liaskou E, Pang H, Xie G, Philips G, Chan IS, Karaca GF, Pereira TD, Chen Y, Mi Z, Kuo PC, Choi SS, Guy CD, Abdelmalek MF, Diehl AM (2012) NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut. Mar 17. [Epub ahead of print]

  32. 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  PubMed  CAS  Google Scholar 

  33. Johnston NI, Gunasekharan VK, Ravindranath A, O’Connell C, Johnston PG, El-Tanani MK. Osteopontin as a target for cancer therapy. Front Biosci. 2008;13:4361–72.

    Article  PubMed  CAS  Google Scholar 

  34. 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. Hepatol. 2012;55:483–90.

    Article  CAS  Google Scholar 

  35. Shahin AA, El Desouky SM, Zayed HS. A retrospective analysis of treatment outcomes in patients with hepatitis C related systemic vasculitis receiving intravenous methylprednisolone and cyclophosphamide. Clin Rheumatol. 2011;30(5):607–14.

    Article  PubMed  Google Scholar 

  36. Cacoub P, Saadoun D, Sene D, Limal N, Piette JC. Treatment of hepatitis C virus related systemic vasculitis. J Rheumatol. 2005;32:11.

    Google Scholar 

  37. Yamamoto N, Nakashima T, Torikai M, Naruse T, Morimoto J, Kon S, Sakai F. Successful treatment of collagen-induced arthritis in nonhuman primates by chimeric anti-osteopontin antibody. Int Immunopharmacol. 2007;7:1460–70.

    Article  PubMed  CAS  Google Scholar 

  38. Nguyen M, Keeffe E. Chronic hepatitis C: genotypes 4 to 9. Clin Liver Dis. 2005;9(3):411–26.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Rheumatology and Rehabilitation, Faculty of Medicine, Cairo University, Cairo, Egypt, 12613

    Iman H. Bassyouni

  2. Medical Microbiology and Immunology Department, El-Fayoum University, Al Fayoum, Egypt

    Rasha H. Bassyouni

  3. Medical Microbiology and Immunology Department, Beni-Swif University, Beni-Swif, Egypt

    Nermin H. Ibrahim

  4. Tropical Department, Faculty of Medicine, Cairo University, Cairo, Egypt

    Ahmed F. Soliman

  5. Rheumatology & Rehabilitation Department, El-Kasr El-Aini Hospital, Cairo, Egypt

    Iman H. Bassyouni

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  1. Iman H. Bassyouni
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Correspondence to Iman H. Bassyouni.

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Bassyouni, I.H., Bassyouni, R.H., Ibrahim, N.H. et al. Elevated Serum Osteopontin Levels in Chronic Hepatitis C Virus Infection: Association with Autoimmune Rheumatologic Manifestations. J Clin Immunol 32, 1262–1269 (2012). https://doi.org/10.1007/s10875-012-9727-7

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  • DOI: https://doi.org/10.1007/s10875-012-9727-7

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