Osteopontin Function in Pathology: Lessons from Osteopontin-Deficient MiceRittling S.R. · Denhardt D.T.
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, N.J., USA
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Osteopontin (OPN) is a soluble secreted phosphoprotein that binds with high affinity to several different integrins. While numerous activities have been ascribed to OPN in vitro, and several in vivo functions have been suggested for the molecule, including much attention focused recently on OPN in different pathologies, the actual role that the protein plays in mammalian physiology remains conjectural. Analysis of recently developed strains of mice lacking OPN because of a targeted disruption of its gene promises to provide important information on this issue. Here, we review the data implicating OPN as functioning in a variety of pathologic conditions as well as the initial results generated with the OPN knockout mice, with particular focus on the question of whether OPN has a protective or a damaging effect in different pathologies. These data will be important to the definition of how OPN contributes to mammalian physiology and pathophysiology.
- Denhardt DT, Guo X: Osteopontin: A protein with diverse functions. FASEB J 1993;7:1475–1482.
- Patarca R, Saavedra RA, Cantor H: Molecular and cellular basis of genetic resistance to bacterial infection: The role of the early T-lymphocyte activation 1/osteopontin gene. Crit Rev Immunol 1993;13:225–246.
- Weber GF, Cantor H: The immunology of Eta–1/osteopontin. Cytokine Growth Factor Rev 1996;7:241–246.
- Giachelli CM, Bae N, Almeida M, Denhardt DT, Alpers CE, Schwartz SM: Osteopontin is elevated during neointima formation in rat arteries and is a novel component of human atherosclerotic plaques. J Clin Invest 1993;92:1686–1696.
- Liaw L, Lindner V, Schwartz SM, Chambers AF, Giachelli CM: Osteopontin and β3 integrin are coordinately expressed in regenerating endothelium in vivo and stimulate Arg-Gly-Asp-dependent endothelial migration in vitro. Circ Res 1995;77:665–672.
- Prince CW, Oosawa T, Butler WT, Tomana M, Bhown AS, Bhown M, Schrohenloher RE: Isolation, characterization and biosynthesis of a phosphorylated glycoprotein from rat bone. J Biol Chem 1987;262:2900–2907.
- Sørensen ES, Hojrup P, Petersen TE: Post-translational modification of bovine osteopontin: Identification of twenty-eight phosphorylation and three O-glycosylation sites. Protein Sci 1995;4:2040–2049.
Butler WT, Ridall AL, McKee MD: Osteopontin; in Bilezikian JP, Raisz LG, Rodan GA (eds): Principles of Bone Biology. San Diego, Academic Press, 1996, pp 167–181.
- 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 αvβ3 in smooth muscle migration to osteopontin in vitro. J Clin Invest 1995;95:713–724.
- Hu DD, Hoyer JR, Smith JW: Calcium suppresses cell adhesion to osteopontin by attenuating binding affinity for integrin αvβ3. J Biol Chem 1995;270:9917–9925.
- Hu DD, Lin ECK, Kovach NL, Hoyer JR, Smith JW: A biochemical characterization of the binding of osteopontin to integrins αvβ1 and αvβ5. J Biol Chem 1995;270:26232–26238.
- Smith LL, Cheung HK, Ling LE, Chen J, Sheppard D, Pytela R, Giachelli CM: Osteopontin N-terminal domain contains a cryptic adhesive sequence recognized by α9β1 integrin. J Biol Chem 1996;271:28485–28491.
- Denda S, Reichardt LF, Müller U: Identification of osteopontin as a novel ligand for the integrin α8β1 and potential roles for this integrin-ligand interaction in kidney morphogenesis. Mol Biol Cell 1998;9:1425–1435.
- Bayless KA, Meininger GA, Scholtz JM, Davis GE: Osteopontin is a ligand for the α4β1 integrin. J Cell Sci 1998;111:1165–1174.
- Weber GF, Ashkar S, Glimcher MJ, Cantor H: Receptor-ligand interaction between CD44 and osteopontin (ETA-1). Science 1996;271:509–512.
- Singh RP, Patarca R, Schwartz J, Singh P, Cantor H: Definition of a specific interaction between the early T lymphocyte activation 1 (Eta-1) protein and murine macrophages in vitro and its effect upon macrophages in vivo. J Exp Med 1990;171:1931–1942.
- Panda D, Kundu GC, Lee BI, Peri A, Fohl D, Chackalaparampil I, Mukherjee BB, Li XD, Mukherjee DC, Seides S, Rosenberg J, Stark K, Mukherjee AB: Potential roles of osteopontin and αvβ3 integrin in the development of coronary artery restenosis after angioplasty. Proc Natl Acad Sci USA 1997;94:9308–9313.
Somerman MJ, Prince CW, Sauk JJ, Foster RA, Butler WT: Cell attachment activity of the 44 kilodalton bone phosphoprotein is not restricted to bone cells. Matrix 1987;9:49–54.
- Chambers AF, Hota C, Prince CW: Adhesion of metastatic, ras-transformed NIH 3T3 cells to osteopontin, fibronectin, and laminin. Cancer Res 1993;53:701–706.
- Senger DR, Perruzzi CA, Papadopoulous-Sergiou A, Van De Water L: Adhesive properties of osteopontin: Regulation by a naturally occurring thrombin-cleavage in close proximity to the GRGDS cell-binding domain. Mol Biol Cell 1994;5:565–574.
- Katagiri YU, Murakami M, Mori K, Iizuka J, Hara T, Tanaka K, Jia WY, Chambers AF, Uede T: Non-RGD domains of osteopontin promote cell adhesion without involving alpha v integrins. J Cell Biochem 1996;62:123–131.
- Liaw L, Almeida M, Hart CE, Schwartz SM, Giachelli CM: Osteopontin promotes vascular cell adhesion and spreading and is chemotactic for smooth muscle cells in vitro. Circ Res 1994;74:214–224.
- Senger DR, Perruzzi CA: Cell migration promoted by a potent GRGDS-containing thrombin-cleavage fragment of osteopontin. Biochim Biophys Acta 1996;1314:13–24.
- 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;269:711–715.
- Rollo EE, Laskin DL, Denhardt DT: Osteopontin inhibits nitric oxide production and cytotoxicity by activated RAW 264.7 macrophages. J Leukoc Biol 1996;60:397–404.
- Lampe MA, Patarca R, Iregui MV, Cantor H: Polyclonal B-cell activation by the Eta-1 cytokine and the development of autoimmune disease. J Immunol 1991;147:2902–2906.
- Bosky AL, Maresca M, Ullrich W, Doty SB, Butler WT, Prince CW: Osteopontin-hydroxyapatite interactions in vitro: Inhibition of hydroxyapatite formation and growth in a gelatin gel. Bone Miner 1993;22:147–159.
- Hunter GK, Hauschka PV, Poole AR, Rosenberg LC, Goldberg HA: Nucleation and inhibition of hydroxyapatite formation by mineralized tissue proteins. Biochem J 1996;317:59–64.
- Shiraga H, Min W, Van Dusen WJ, Clayman MD, Miner D, Terrell CH, Sherbotie JR, Foreman JW, Przysiecki C, Neilson EG, Hoyer JR: Inhibition of calcium oxalate crystal growth in vitro by uropontin, a new member of the aspartic-acid rich protein superfamily. Proc Natl Acad Sci USA 1992;89:426–430.
- Worcester EM, Blumenthal SS, Beshensky AM, Lewand DL: The calcium oxalate crystal growth inhibitor protein produced by mouse kidney cortical cells in culture is osteopontin. J Bone Miner Res 1992;7:1029–1036.
- Scatena M, Almeida M, Chaisson ML, Fausto N, Nicosia RF, Giachelli CM: NF-κB mediates αvβ3 integrin-induced endothelial cell survival. J Cell Biol 1998;141:1083–1093.
- Rittling SR, Matsumoto HN, McKee MD, Nanci A, An XR, Novick KE, Kowalski AJ, Noda M, Denhardt DT: Mice lacking osteopontin show normal development and bone structure but display altered osteoclast formation in vitro. J Bone Miner Res 1998;13:1101–1111.
Liaw L, Birk DE, Ballas CB, Whitsitt JS, Davidson JM, Hogan BLM: Altered wound healing in mice lacking a functional osteopontin gene (spp1). J Clin Invest 1998;101:1468–1478.
Rodan GA: Osteopontin overview. Ann NY Acad Sci 1995;760:1–5.
- Nomura S, Wills AJ, Edwards DR, Heath JK, Hogan BLM: Developmental expression of 2ar (osteopontin) and SPARC (osteonectin) RNA as revealed by in situ hybridization. J Cell Biol 1988;106:441–450.
- Stern DN, Glimcher MJ, Saavedra RA: Localization of osteopontin during mouse development. Ann NY Acad Sci 1995;760:367–370.
- Rogers SA, Padanilam BJ, Hruska KA, Giachelli CM, Hammerman MR: Metanephric osteopontin regulates nephrogenesis in vitro. Am J Physiol 1997;272:F469–F476.
- Rittling SR, Novick KW: Osteopontin expression in mammary gland development and tumorigenesis. Cell Growth Differ 1997;8:1061–1069.
- Rittling SR, Feng F: Detection of mouse osteopontin by Western blotting. Biochem Biophys Res Commun 1998;250:287–292.
- Wesson JA, Worcester EM, Weissner JH, Mandel NS, Kleinman JG: Control of calcium oxalate crystal structure and cell adherence by urinary macromolecules. Kidney Int 1998;53:952–957.
- Kleinman JG, Beshensky AM, Worcester EM, Brown D: Expression of osteopontin, a urinary inhibitor of stone mineral crystal growth, in rat kidney. Kidney Int 1995;47:1585–1596.
- Lopez CA, Hoyer JR, Wilson PD, Waterhouse P, Denhardt DT: Heterogeneity of osteopontin expression among nephrons in mouse kidneys and enhanced expression in sclerotic glomeruli. Lab Invest 1993;69:355–363.
- Giachelli CM, Pichler R, Lombardi D, Denhardt DT, Alpers CE, Schwartz SM, Johnson RJ: Osteopontin expression in angiotensin II-induced tubulointerstitial nephritis. Kidney Int 1994;45:515–524.
- Pichler R, Giachelli CM, Lombardi D, Pippin J, Gordon K, Alpers CE, Schwartz SM, Johnson RJ: Tubulointerstitial disease in glomerulonephritis: Potential role of osteopontin. Am J Pathol 1994;144:915–926.
- Pichler R, Franceschini N, Young BA, Hugo C, Andoh TF, Burdmann EA, Shankland SJ, Alpers CE, Bennett WM, Couser WG: Pathogenesis of cyclosporine nephropathy: Roles of angiotensin II and osteopontin. J Am Soc Nephrol 1995;6:1186–1196.
- Eddy AA, Giachelli CM: Renal expression of genes that promote interstitial inflammation and fibrosis in rats with protein-overload proteinuria. Kidney Int 1995;47:1546–1557.
Diamond JR, Kees-Folts D, Ricardo SD, Eufemio M: Early and persistent up-regulated expression of renal cortical osteopontin in experimental hydronephrosis. Am J Physiol 1995;146:1455–1466.
- Lan HY, Yu XQ, Yang N, Nikolic-Paterson DJ, Mu W, Pichler R, Johnson RJ, Atkins RC: De novo glomerular osteopontin expression in rat crescentic glomerulonephritis. Kidney Int 1998;53:136–145.
- Nambi P, Gellai M, Wu HL, Prabhakar U: Upregulation of osteopontin in ischemia-induced renal failure in rats: A role for ET-1? Biochem Biophys Res Commun 1997;241:212–214.
- Noiri E, Peresleni T, Miller F, Goligorsky MS: In vivo targeting of inducible iNOS synthase with oligodeoxynucleotides protects rat kidney against ischemia. J Clin Invest 1996;97:2377–2383.
Noiri E, Dickman K, Miller F, Romanov G, Romanov V, Shaw R, Rittling SR, Denhardt DT, Goligorsky MS: Acute renal ischemia in mice with a targeted disruption of the osteopontin gene: Link to nitric oxide-induced injury. Kidney Int, in press.
Ophascharoensuk V, Giachelli CM, Liaw L, Shankland SJ, Couser WG, Johnson RJ: Osteopontin (OPN) mediates early macrophage influx in renal interstitial inflammation: A study in OPN knockout (KO) mice (abstract). J Am Soc Nephrol 1997;8:481.
- Yu XQ, Nikolic-Paterson DJ, Mu W, Giachelli CM, Atkins RC, Johnson RJ, Lan HY: A functional role for osteopontin in experimental crescentic glomerulonephritis in the rat. Proc Assoc Am Physicians 1998;110:50–64.
Giachelli CM, Schwartz SM, Liaw L: Molecular and cellular biology of osteopontin. Trends Cardiovasc Med 1995;5:88–95.
- Wang X, Louden C, Yue TL, Ellison JA, Barone FC, Solleveld HA, Feuerstein GZ: Delayed expression of osteopontin after focal stroke in the rat. J Neurosci 1998;18:2075–2083.
- Williams EB, Halpert I, Wickline S, Davison G, Parks WC, Rottman JN: Osteopontin expression is increased in the heritable cardiomyopathy of Syrian hamsters. Circulation 1995;92:705–709.
- Senger DR, Asch BB, Smith BD, Perruzzi CA, Dvorak HF: A secreted phosphoprotein marker for neoplastic transformation of both epithelial and fibroblastic cells. Nature 1983;302:714–715.
- Brown LF, Papadopoulous-Sergiou A, Berse B, Manseau EJ, Tognazzi K, Perruzzi CA, Dvorak HF, Senger DR: Osteopontin expression and distribution in human carcinomas. Am J Pathol 1994;145:610–623.
- Bellahcène A, Castronovo V: Increased expression of osteonectin and osteopontin, two bone matrix proteins, in human breast cancer. Am J Pathol 1995;146:95–100.
- Senger DR, Perruzzi CA, Papadopoulous A: Elevated expression of secreted phosphoprotein I (osteopontin, 2ar) as a consequence of neoplastic transformation. Anticancer Res 1989;9:1291–1300.
- Chambers AF, Behrend EI, Wilson SM, Denhardt DT: Induction of expression of osteopontin (OPN, secreted phosphoprotein) in metastatic, ras-transformed NIH-3T3 cells. Anticancer Res 1992;12:43–48.
- Guo X, Zhang YP, Mitchell DA, Denhardt DT, Chambers AF: Identification of a ras-activated enhancer in the mouse osteopontin promoter and its interaction with a putative ETS-related transcription factor whose activity correlates with the metastatic potential of the cell. Mol Cell Biol 1995;15:476–487.
- Denhardt DT, Chambers AF: Overcoming obstacles to metastasis – a defense against host defenses: Osteopontin (OPN) as a shield against attack by cytotoxic host cells. J Cell Biochem 1994;56:48–51.
- Montgomery AM, Reisfeld RA, Cheresh DA: Integrin alpha v beta 3 rescues melanoma cells from apoptosis in three-dimensional dermal collagen. Proc Natl Acad Sci USA 1994;91:8856–8860.
- Behrend EI, Craig AM, Wilson SM, Denhardt DT, Chambers AF: Reduced malignancy of ras-transformed NIH 3T3 cells expressing antisense osteopontin RNA. Cancer Res 1994;54:832–837.
- Gardner HAR, Berse B, Senger DR: Specific reduction in osteopontin synthesis by antisense RNA inhibits the tumorigenicity of transformed Rat1 fibroblasts. Oncogene 1994;9:2321–2326.
- Su L, Mukherjee AB, Mukherjee BB: Expression of antisense osteopontin mRNA inhibits tumor promoter-induced neoplastic transformation of mouse JB6 epidermal cells. Oncogene 1995;10:2163–2169.
Wu YM, Denhardt DT, Rittling SR: Attenuation of the transformation phenotype in the absence of osteopontin, in preparation.
- Miyazaki Y, Setoguchi S, Yoshida S, Higuchi Y, Akizuki S, Yamamoto S: The mouse osteopontin gene: Expression in monocytic lineages and complete nucleotide sequence. J Biol Chem 1990;265:14432–14438.
- Rollo EE, Denhardt DT: Differential effects of osteopontin on the cytotoxic activity of macrophages from young and old mice. Immunology 1996;88:642–647.
- Krause SW, Rehli M, Kreutz M, Schwarzfischer L, Paulauskis JD, Andreesen R: Differential screening identifies genetic markers of monocyte to macrophage maturation. J Leukoc Biol 1996;60:540–545.
- Giachelli CM, Lombardi D, Johnson RJ, Murry CE, Almeida M: Evidence for a role of osteopontin in macrophage infiltration in response to pathological stimuli in vivo. Am J Pathol 1998;152:353–358.
Tian JY, Sørensen ES, Butler WT, Lopez CA, Sy MS, Denhardt DT: Regulation of NO synthesis induced by inflammatory mediators in RAW 264.7 cells: collagen blocks inhibition by osteopontin, submitted.
Yoshitake H, Rittling SR, Denhardt DT, Noda M: Osteopontin-deficient mice are resistant to ovariectomy-induced bone resorption, submitted.
Väänänen K: Osteoclast function: Biology and mechanism; in Bilezikian JP, Raisz LG, Rodan GA (eds): Principles of Bone Biology. San Diego, Academic Press, 1996, pp 103–114.
- Flores M, Norgard M, Heinegård D, Reinholt FP, Andersson G: RGD-directed attachment of rat osteoclasts to osteopontin, bone sialoprotein and fibronectin. Exp Cell Res 1992;201:526–530.
- Ross FP, Chappel J, Alvarez JI, Sander D, Butler WT, Farach-Carson MC, Mintz KA, Robey PG, Teitelbaum SL: Interactions between the bone matrix proteins osteopontin and bone sialoprotein and the osteoclast integrin αvβ3 potentiate bone resorption. J Biol Chem 1993;268:9901–9907.
- Miyauchi A, Alvarez JI, Greenfield EM, Teti A, Grano M, Colucci S, Zambonin-Zallone A, Ross FP, Teitelbaum SL, Cheresh DA, Hruska KA: Recognition of osteopontin and related peptides by an αvβ3 integrin stimulates immediate cell signals in osteoclasts. J Biol Chem 1991;266:20369–20374.
- Matsumoto HN, Tamura M, Denhardt DT, Obinata M, Noda M: Establishment and characterization of bone marrow stromal cell lines that support osteoclastogenesis. Endocrinology 1995;136:4084–4091.
- Chackalaparampil I, Peri A, Nemir M, McKee MD, Lin PH, Mukherjee BB, Mukherjee AB: Cells in vivo and in vitro from osteopetrotic mice homozygous for c-src disruption show suppression of synthesis of osteopontin, a multifunctional extracellular matrix protein. Oncogene 1996;12:1457–1467.
Rollo EE, Hempson SJ, Rittling SR, Denhardt DT, Mackow ER, Shaw RD: The extracellular matrix protein osteopontin is an element of the host mucosal defense against rotavirus diarrhea, in preparation.
- Juliano RL, Haskill S: Signal transduction from the extracellular matrix. J Cell Biol 1993;120:577–585.
- Zheng X, Saunders TL, Camper SA, Samuelson LC, Ginsburg D: Vitronectin is not essential for normal mammalian development and fertility. Proc Natl Acad Sci USA 1995;92:12426–12430.
- Saga Y, Yagi T, Ikawa Y, Sakakura T, Aizawa S: Mice develop normally without tenascin. Genes Dev 1992;6:1821–1831.
- Lawler J, Sunday M, Thibert V, Duquette M, George EL, Rayburn H, Hynes RO: Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J Clin Invest 1998;101:982–992.
- Gilmour DT, Lyon GJ, Carlton MB, Sanes JR, Cunningham JM, Anderson JR, Hogan BL, Evans MJ, Colledge WH: Mice deficient for the secreted glycoprotein SPARC/osteonectin/BM40 develop normally but show severe age-onset cataract formation and disruption of the lens. EMBO J 1998;17:1860–1870.
- Murry CE, Giachelli CM, Schwartz SM, Vracko R: Macrophages express osteopontin during repair of myocardial necrosis. Am J Pathol 1994;145:1450–1462.
- O’Brien ER, Garvin MR, Stewart DK, Hinohara T, Simpson JB, Schwartz SM, Giachelli CM: Osteopontin is synthesized by macrophage, smooth muscle, and endothelial cells in primary and restenotic human coronary atherosclerotic plaques. Arterioscler Thromb 1994;14:1648–1656.
- Carlson I, Tognazzi K, Manseau EJ, Dvorak HF, Brown LF: Osteopontin is strongly expressed by histiocytes in granulomas of diverse etiology. Lab Invest 1997;77:103–108.
- Nau GJ, Guilfoile P, Chupp GL, Berman JS, Kim SJ, Kornfield H, Young RA: A chemoattractant cytokine associated with granulomas in tuberculosis and silicosis. Proc Natl Acad Sci USA 1997;94:6414–6419.
- McKee MD, Nanci A: Secretion of osteopontin by macrophages and its accumulation at tissue surfaces during wound healing in mineralized tissues: A potential requirement for macrophage adhesion and phagocytosis. Anat Rec 1996;245:394–409.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.