Osteopontin and cardiovascular system Authors
First Online: 30 November 2006 Received: 08 September 2006 Accepted: 25 October 2006 DOI:
Cite this article as: Okamoto, H. Mol Cell Biochem (2007) 300: 1. doi:10.1007/s11010-006-9368-3 Abstract
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.
Keywords Extracellular matrix (ECM) Matricellular proteins Osteopontin (OPN) Remodeling References
Frisch SM, Screaton RA (2001) Anoikis mechanisms. Curr Opin Cell Biol 13(5):555–562
Schellings MW, Pinto YM, Heymans S (2004) Matricellular proteins in the heart: possible role during stress and remodeling. Cardiovasc Res 64(1):24–31
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):860–864
Denhardt DT, Guo X (1993) Osteopontin: a protein with diverse functions. FASEB J 7:1475–1482
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 294:1731–1735
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):2061–2067
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):319–332
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):491–502
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):1453–1459
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):680–690
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):1055–1061
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 59:219–226
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):509–512
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):36328–36334
Xie Z, Singh M, Singh K (2004) Osteopontin modulates myocardial hypertrophy response to chronic pressure overload in mice. Hypertension 44:826–831
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 98:2218–2227
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 278:48546–48552
Murry CE, Giachelli CM, Schwartz SM, Vracko R (1994) Macrophages express osteopontin during repair of myocardial necrosis. Am J Pathol 145:1450–1462
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):705–709
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 101:1468–1478
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):399–407
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 88:1080–1087
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 43:1195–1201
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 4:139–146
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 7:755–762
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: 2814–2820
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 17:188–193
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 16:111–117
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):1029–1034
Mohler ER 3rd, Adam LP, McClelland P, Graham L, Hathaway DR (1997) Detection of osteopontin in calcified human aortic valves. Arterioscler Thromb Vasc Biol 17:547–552
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):1047–1105
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):1564–1573
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 287:1671–1679
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 145:33–40
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 18:1–6
Rho J, Takami M, Choi Y (2004) Osteoimmunology: interactions of the immune and skeletal systems. Mol Cells 17(1):1–9
PubMed Copyright information
© Springer Science+Business Media, LLC 2006