Molecular and Cellular Biochemistry

, Volume 300, Issue 1–2, pp 1–7

Osteopontin and cardiovascular system



A matricellular protein, osteopontin (OPN), is expressed in response to mechanical stress and similar stimuli in the heart, integrates the inter-ECM signal transduction network of component cells, and maintains efficient contractility through quantitative and qualitative control of extracellular matrix (ECM) proteins. In particular, OPN is re-expressed in the process of tissue damage; combines with other cell growth factors, cytokines, chemokines, and proteases as a cytokine itself or as an adhesion molecule; and controls the differentiation and growth of cells involved in re-storation of tissues by controlling inter-cellular signal transduction and production of ECM proteins through regulation of expression levels and activity. A study using mice lacking a functional OPN gene indicated that tissue restoration fails and collagen deposition is inhibited through matrix metalloproteinases (MMPs) in mice lacking OPN. Thus, while OPN accelerates the cardiovascular remodeling process, it also regulates the balance of various inter-cellular activities. In addition, OPN not only promotes arteriosclerosis but is also closely associated with angiogenesis. With the roles of OPN expected to be clinically elucidated, the clinical use of OPN for control of cardiovascular remodeling may be feasible.

Points (1) Osteopontin (OPN) efficiently propagates contraction in the heart as a matricellular protein and thereby controls ECM proteins both quantitatively and qualitatively.

(2) The quantitative and qualitative control of ECM proteins is involved in interaction with OPN receptors including those of the integrin family, CD44, and others.

(3) OPN promotes myocardial remodeling through TGFβ and MMPs.

(4) OPN not only promotes arteriosclerosis but is also closely associated with arteriosteogenesis.

(5) In animals lacking OPN, tissue remodeling process is inhibited, especially in terms of fibrosis after myocardial infarction.

(6) While the significance of OPN as an immune system molecule is still unclear in detail, the significance of OPN in the regenerative immune system has begun to be determined.


Extracellular matrix (ECM) Matricellular proteins Osteopontin (OPN) Remodeling 


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  1. 1.
    Frisch SM, Screaton RA (2001) Anoikis mechanisms. Curr Opin Cell Biol 13(5):555–562PubMedCrossRefGoogle Scholar
  2. 2.
    Schellings MW, Pinto YM, Heymans S (2004) Matricellular proteins in the heart: possible role during stress and remodeling. Cardiovasc Res 64(1):24–31PubMedCrossRefGoogle Scholar
  3. 3.
    Ashkar S, Weber GF, Panoutsakopoulou V, Sanchirico ME, Jansson M, Zawaideh S, Rittling SR, Denhardt DT, Glimcher MJ, Cantor H (2000) Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science 287(5454):860–864PubMedCrossRefGoogle Scholar
  4. 4.
    Denhardt DT, Guo X (1993) Osteopontin: a protein with diverse functions. FASEB J 7:1475–1482PubMedGoogle Scholar
  5. 5.
    Chabas D, Baranzini SE, Mitchell D, Bernard CC, Rittling SR, Denhardt DT, Sobel RA, Lock C, Karpuj M, Pedotti R, Heller R, Oksenberg JR, Steinman L (2001) The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294:1731–1735PubMedCrossRefGoogle Scholar
  6. 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 (2002) Enhanced local production of osteopontin in rheumatoid joints. J Rheumatol 29(10):2061–2067PubMedGoogle Scholar
  7. 7.
    Chiba S, Rashid MM, Okamoto H, Shiraiwa H, Kon S, Maeda M, Murakami M, Inobe M, Kitabatake A, Chambers AF, Uede T (2000) The role of osteopontin in the development of granulomatous lesions in lung. Microbiol Immunol 44(4):319–332PubMedGoogle Scholar
  8. 8.
    Young MF, Kerr JM, Termine JD, Wewer UM, Wang MG, McBride OW, Fisher LW (1990) cDNA cloning, mRNA distribution and heterogeneity, chromosomal location, and RFLP analysis of human osteopontin (OPN). Genomics 7(4):491–502PubMedCrossRefGoogle Scholar
  9. 9.
    Kubota T, Zhang Q, Wrana JL, Ber R, Aubin JE, Butler WT, Sodek J (1989) Multiple forms of SppI (secreted phosphoprotein, osteopontin) synthesized by normal and transformed rat bone cell populations: regulation by TGF-beta. Biochem Biophys Res Commun 162(3):1453–1459PubMedCrossRefGoogle Scholar
  10. 10.
    Xuan JW, Hota C, Shigeyama Y, D’Errico JA, Somerman MJ, Chambers AF (1995) Site-directed mutagenesis of the arginine-glycine-aspartic acid sequence in osteopontin destroys cell adhesion and migration functions. J Cell Biochem 57(4):680–690PubMedCrossRefGoogle Scholar
  11. 11.
    Denhardt DT, Noda M, O’Regan AW, Pavlin D, Berman JS (2001) Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. J Clin Invest 107(9):1055–1061PubMedGoogle Scholar
  12. 12.
    Yohko UK, Jonathan S, Hideki F, Peter H, Hiroshi H, Kumiko T, Shunsuke C, Hideo Y, Ko O, Masaaki M, Ikuo S, Ann FC, Toshimitsu U (1999) CD44 variants but not CD44s cooperate with ß1-containing integrins to permit cells to bind to osteopontin independently of arginine-glycine-aspartic acid, thereby stimulating cell motility and chemotaxis. Cancer Res 59:219–226Google Scholar
  13. 13.
    Weber GF, Zawaideh S, Hikita S, Kumar VA, Cantor H, Ashkar S (1996) Receptor-ligand interaction between CD44 and osteopontin (Eta-1). Science 271(5248):509–512PubMedCrossRefGoogle Scholar
  14. 14.
    Yokosaki Y, Matsuura N, Sasaki T, Murakami I, Schneider H, Higashiyama S, Saitoh Y, Yamakido M, Taooka Y, Sheppard D (1999) The integrin α9ß1 binds to a novel recognition sequence (SVVYGLR) in the n-cleaved amino-terminal fragment of osteopontin. J Biol Chem 274(51):36328–36334PubMedCrossRefGoogle Scholar
  15. 15.
    Xie Z, Singh M, Singh K (2004) Osteopontin modulates myocardial hypertrophy response to chronic pressure overload in mice. Hypertension 44:826–831PubMedCrossRefGoogle Scholar
  16. 16.
    Ashizawa N, Graf K, Do YS, Nunohiro T, Giachelli CM, Meehan WP, Tuan TL, Hsueh WA (1996) Osteopontin is produced by rat cardiac fibroblasts and mediates A(II)-induced DNA synthesis and collagen gel contraction. J Clin Invest 98:2218–2227PubMedGoogle Scholar
  17. 17.
    Xie Z, Singh M, Siwik DA, Joyner WL, Singh K (2003) Osteopontin inhibits IL-1beta-stimulated increases in matrix metalloproteinase activity in adult rat cardiac fibroblasts: role of protein kinase C-zeta. J Biol Chem 278:48546–48552PubMedCrossRefGoogle Scholar
  18. 18.
    Murry CE, Giachelli CM, Schwartz SM, Vracko R (1994) Macrophages express osteopontin during repair of myocardial necrosis. Am J Pathol 145:1450–1462PubMedGoogle Scholar
  19. 19.
    Williams EB, Halpert I, Wickline S, Davison G, Parks WC, Rottman JN (1995) Osteopontin expression is increased in the heritable cardiomyopathy of Syrian hamsters. Circulation 92(4):705–709PubMedGoogle Scholar
  20. 20.
    Liaw L, Birk DE, Ballas CB, Whitsitt JS, Davidson JM, Hogan BL (1998) Altered wound healing in mice lacking a functional osteopontin gene (spp1). J Clin Invest 101:1468–1478PubMedGoogle Scholar
  21. 21.
    Xie Z, Singh M, Singh K (2004) ERK1/2 and JNKs, but not p38 kinase, are involved in reactive oxygen species-mediated induction of osteopontin gene expression by angiotensin II and interleukin-1beta in adult rat cardiac fibroblasts. J Cell Physiol 198(3):399–407PubMedCrossRefGoogle Scholar
  22. 22.
    Trueblood NA, Xie Z, Communal C, Sam F, Ngoy S, Liaw L, Jenkins AW, Wang J, Sawyer DB, Bing OH, Apstein CS, Colucci WS, Singh K (2001) Exaggerated left ventricular dilation and reduced collagen deposition after myocardial infarction in mice lacking osteopontin. Circ Res 88:1080–1087PubMedGoogle Scholar
  23. 23.
    Matsui Y, Jia N, Okamoto H, Kon S, Onozuka H, Akino M, Liu L, Morimoto J, Rittling SR, Denhardt D, Kitabatake A, Uede T (2004) Role of osteopontin in cardiac fibrosis and remodeling in angiotensin II-induced cardiac hypertrophy. Hypertension 43:1195–1201PubMedCrossRefGoogle Scholar
  24. 24.
    Stawowy P, Blaschke F, Pfautsch P, Goetze S, Lippek F, Wollert-Wulf B, Fleck E, Graf K (2002) Increased myocardial expression of osteopontin in patients with advanced heart failure. Eur J Heart Fail 4:139–146PubMedCrossRefGoogle Scholar
  25. 25.
    Satoh M, Nakamura M, Akatsu T, Shimoda Y, Segawa I, Hiramori K (2005) Myocardial osteopontin expression is associated with collagen fibrillogenesis in human dilated cardiomyopathy. Eur J Heart Fail 7:755–762PubMedCrossRefGoogle Scholar
  26. 26.
    Ikeda T, Shirasawa T, Esaki Y, Yoshiki S, Hirokawa K (1993) Osteopontin mRNA is expressed by smooth muscle-derived foamy cells in human atherosclerotic lesions of the aorta. J Clin Invest 92: 2814–2820PubMedCrossRefGoogle Scholar
  27. 27.
    Liaw L, Lombardi DM, Almeida MM, Schwartz SM, deBlois D, Giachelli CM (1997) Neutralizing antibodies directed against osteopontin inhibit rat carotid neointimal thickening after endothelial denudation. Arterioscler Thromb Vasc Biol 17:188–193PubMedGoogle Scholar
  28. 28.
    Chiba S, Okamoto H, Kon S, Kimura C, Murakami M, Inobe M, Matsui Y, Sugawara T, Shimizu T, Uede T, Kitabatake A (2002) Development of atherosclerosis in osteopontin transgenic mice. Heart Vessels 16:111–117PubMedCrossRefGoogle Scholar
  29. 29.
    Matsui Y, Rittling SR, Okamoto H, Inobe M, Jia N, Shimizu T, Akino M, Sugawara T, Morimoto J, Kimura C, Kon S, Denhardt D, Kitabatake A, Uede T (2003) Osteopontin deficiency attenuates atherosclerosis in female apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 23(6):1029–1034PubMedCrossRefGoogle Scholar
  30. 30.
    Mohler ER 3rd, Adam LP, McClelland P, Graham L, Hathaway DR (1997) Detection of osteopontin in calcified human aortic valves. Arterioscler Thromb Vasc Biol 17:547–552PubMedGoogle Scholar
  31. 31.
    Speer MY, McKee MD, Guldberg RE, Liaw L, Yang HY, Tung E, Karsenty G, Giachelli CM (2002) Inactivation of the osteopontin gene enhances vascular calcification of matrix Gla protein-deficient mice: evidence for osteopontin as an inducible inhibitor of vascular calcification in vivo. J Exp Med 196(8):1047–1105PubMedCrossRefGoogle Scholar
  32. 32.
    Pass HI, Lott D, Lonardo F, Harbut M, Liu Z, Tang N, Carbone M, Webb C, Wali A (2005) Asbestos exposure, pleural mesothelioma, and serum osteopontin levels. N Engl J Med 353(15):1564–1573PubMedCrossRefGoogle Scholar
  33. 33.
    Kim JH, Skates SJ, Uede T, Wong KK, Schorge JO, Feltmate CM, Berkowitz RS, Cramer DW, Mok SC (2002) Osteopontin as a potential diagnostic biomarker for ovarian cancer. JAMA 287:1671–1679PubMedCrossRefGoogle Scholar
  34. 34.
    Suezawa C, Kusachi S, Murakami T, Toeda K, Hirohata S, Nakamura K, Yamamoto K, Koten K, Miyoshi T, Shiratori Y (2005) Time-dependent changes in plasma osteopontin levels in patients with anterior-wall acute myocardial infarction after successful reperfusion: correlation with left-ventricular volume and function. J Lab Clin Med 145:33–40PubMedCrossRefGoogle Scholar
  35. 35.
    Minoretti P, Falcone C, Calcagnino M, Emanuele E, Buzzi MP, Coen E, Geroldi D (2006) Prognostic significance of plasma osteopontin levels in patients with chronic stable angina. Eur Heart J 18:1–6Google Scholar
  36. 36.
    Rho J, Takami M, Choi Y (2004) Osteoimmunology: interactions of the immune and skeletal systems. Mol Cells 17(1):1–9PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  1. 1.Department of Cardiovascular MedicineHokkaido University Graduate School of MedicineSapporoJapan

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