Osteopontin (OPN) is a phosphorylated protein of wide tissue distribution that is found in association with dystrophic calcification including in the organic matrix of kidney stones. It is a strong inhibitor of crystal formation and growth in vitro, but there is still debate regarding its effects upon crystal adhesion to tubular epithelial cells. In this brief review, we will outline the evidence implicating OPN in stone disease with the primary emphasis being on the interaction of OPN with calcium oxalate (CaOx), the major constituent of calcium containing stones. Finally, preliminary data is presented regarding the amounts and features of OPN present in the urine of stone formers and normal individuals.

Keywords:
Osteopontin, Kidney calculi, Nephrolithiasis, Calcium oxalate, Crystal formation
1.
Rittling SR, Denhardt DT: Osteopontin function in pathology: Lessons from osteopontin-deficient mice. Exp Nephrol 1999;7:103–113.
2.
Mazzali M, Kipari T, Ophascharoensuk V, Wesson JA, Johnson R, Hughes J: Osteopontin – a molecule for all seasons. QJM 2002;95:3–13.
3.
Kohri K, Suzuki Y, Yoshida K, Yamamoto K, Amasaki N, Yamate T, Umekawa T, Iguchi M, Sinohara H, Kurita T: Molecular cloning and sequencing of cDNA encoding urinary stone protein, which is identical to osteopontin. Biochem Biophys Res Commun 1992;184:859–864.
4.
Kohri K, Nomura S, Kitamura Y, Nagata T, Yoshioka K, Iguchi M, Yamate T, Umekawa T, Suzuki Y, Sinohara H, Kurita T: Structure and expression of the mRNA encoding urinary stone protein (osteopontin). J Biol Chem 1993;268:15180–15184.
5.
Umekawa T, Yamate T, Amasaki N, Kohri K, Kurita T: Osteopontin mRNA in the kidney on an experimental rat model of renal stone formation without renal failure. Urol Int 1995;55:6–10.
6.
Umekawa T, Kohri K, Kurita T, Hirota S, Nomura S, Kitamura Y: Expression of osteopontin messenger RNA in the rat kidney on experimental model of renal stone. Biochem Mol Biol Int 1995;35:223–230.
7.
McKee MD, Nanci A, Khan SR: Ultrastructural immunodetection of osteopontin and osteocalcin as major matrix components of renal calculi. J Bone Miner Res 1995;10:1913–1929.
8.
Atmani F, Opalko FJ, Khan SR: Association of urinary macromolecules with calcium oxalate crystals induced in vitro in normal human and rat urine. Urol Res 1996;24:45–50.
9.
Atmani F, Glenton PA, Khan SR: Identification of proteins extracted from calcium oxalate and calcium phosphate crystals induced in the urine of healthy and stone forming subjects. Urol Res 1998;26:201–207.
10.
Khan SR, Johnson JM, Peck AB, Cornelius JG, Glenton PA: Expression of osteopontin in rat kidneys: Induction during ethylene glycol induced calcium oxalate nephrolithiasis. J Urol 2002;168:1173–1181.
11.
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.
12.
Shiraga H, Min W, VanDusen 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: Another member of the aspartic acid-rich protein superfamily. Proc Natl Acad Sci USA 1992;89:426–430.
13.
Worcester EM, Beshensky AM: Osteopontin inhibits nucleation of calcium oxalate crystals. Ann NY Acad Sci 1995;760:375–377.
14.
Yamate T, Kohri K, Umekawa T, Amasaki N, Isikawa Y, Kurita T: The effect of osteopontin on the adhesion of calcium oxalate crystals to Madin-Darby canine kidney cells. Eur Urol 1996;30:388–393.
15.
Yasui T, Fujita K, Asai K, Kohri K: Osteopontin regulates adhesion of calcium oxalate crystals to renal epithelial cells. Int J Urol 2002;9:100–108.
16.
Lieske JC, Leonard R, Toback FG: Adhesion of calcium oxalate monohydrate crystals to renal epithelial cells is inhibitied by specific anions. Am J Physiol 1995;268:F604–F612.
17.
Verhulst A, Asselman M, Persy VP, Schepers MS, Helbert MF, Verkoelen CF, De Broe ME: Crystal retention capacity of cells in the human nephron: Involvement of CD44 and its ligands hyaluronic acid and osteopontin in the transition of a crystal binding into a nonadherent epithelium. J Am Soc Nephrol 2003;14:107–115.
18.
Konya E, Umekawa T, Iguchi M, Kurita T: The role of osteopontin on calcium oxalate crystal formation. Eur Urol 2003;43:564–571.
19.
Kleinman JG, Beshensky A, Worcester EM, Brown D: Expression of osteopontin, a urinary inhibitor of stone mineral crystal growth. Kidney Int 1995;47:1585–1596.
20.
Wesson JA, Worcester EM, Wiessner JH, Mandel NS, Kleinman JG: Control of calcium oxalate crystal structure and cell adherence by urinary macromolecules. Kidney Int 1998;53:952–957.
21.
Wesson JA, Johnson RJMM, Beshensky AM, Stietz S, Giachelli C, Liaw L, Alpers CE, Couser WG, Kleinman JG, Hughes J: Osteopontin is a critical inhibitor of calcium oxalate crystal formation and retention in renal tubules. J Am Soc Nephrol 2003;14:139–147.
22.
Gokhale JA, Glenton PA, Khan SR: Localization of Tamm-Horsfall protein and osteopontin in a rat nephrolithiasis model. Nephron 1996;73:456–461.
23.
Yagisawa T, Chandhoke PS, Fan J, Lucia S: Renal osteopontin expression in experimental urolithiasis. J Endourol 1998;12:171–176.
24.
Puleo DA, Preston KE, Shaffer JB, Bizios R: Examination of osteoblast-orthopaedic biomaterial interactions using molecular techniques. Biomaterials 1993;14:111–114.
25.
Kumar S, Sigmon D, Miller T, Carpenter B, Khan S, Malhotra R, ScheidC, Menon M: A new model of nephrolithiasis involving tubular dysfunction/injury. J Urol 1991;146:1384–1389.
26.
Ophascharoensuk V, Giachelli CM, Gordon K, Hughes J, Pichler R, Brown P, Liaw L, Schmidt R, Shankland SJ, Alpers CE, Couser WG, Johnson RJ: Obstructive uropathy in the mouse: Role of osteopontin in interstitial fibrosis and apoptosis. Kidney Int 1999;56:571–580.
27.
Khan SA, Lopez-Chua CA, Zhang J, Fisher LW, Sorensen ES, Denhardt DT: Soluble osteopontin inhibits apoptosis of adherent endothelial cells deprived of growth factors. J Cell Biochem 2002;85:728–736.
28.
Denhardt DT, Noda M, O’Regan AW, Pavlin D, Berman JS: Osteopontin as a means to cope with environmental insults: Regulation of inflammation, tissue remodeling, and cell survival (review, 40 refs). J Clin Invest 2001;107:1055–1061.
29.
Steitz SA, Speer MY, McKee MD, Liaw L, Almeida M, Yang H, Giachelli CM: Osteopontin inhibits mineral deposition and promotes regression of ectopic calcification. Am J Pathol 2002;161:2035–2046.
30.
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.
31.
Yoon K, Buenaga R, Rodan GA: Tissue specificity and developmental expression of rat osteopontin. Biochem Biophys Res Commun 1987;148:1129–1136.
32.
Craig AM, Smith JH, Denhardt DT: Osteopontin, a transformation-associated cell adhesion phosphoprotein, is induced by 12-O-tetradecanoylphorbol 13-acetate in mouse epidermis. J Biol Chem 1989;264:9682–9689.
33.
Senger DR, Perruzzi CA, Papadopoulos A, Tenen DG: Purification of a human milk protein closely similar to tumor-secreted phosphoproteins and osteopontin. Biochim Biophys Acta 1989;996:43–48.
34.
Barak-Shalom T, Schickler M, Knopov V, Shapira R, Hurwitz S, Pines M: Synthesis and phosphorylation of osteopontin by avian epiphyseal growth-plate chondrocytes as affected by differentiation. Comp Biochem Physiol 1995;111C:49–59.
35.
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.
36.
Kleinman JG, Worcester EM, Beshensky AM, Sheridan AM, Bonventre JV, Brown D: Upregulation of osteopontin expression by ischemia in rat kidney. Ann NY Acad Sci 1995;760:321–323.
37.
Riese RJ, Mandel NS, Wiessner JH, Mandel GS, Becker CG, Kleinman JG: Cell polarity and calcium oxalate crystal adherence to cultured collecting duct cells. Am J Physiol 1992;262/31:F117–F184.
38.
Denhardt DT, Guo X: Osteopontin: A protein with diverse functions. FASEB J 1993;7:1475–1482.
39.
Nagata T, Todescan R, Goldberg HA, Zhang Q, Sodek J: Sulphation of secreted phosphoprotein I (SPPI, osteopontin) is associated with mineralized tissue formation. Biochem Biophys Res Commun 1989;165:234–240.
40.
Fisher LW, Torchia DA, Fohr B, Young MF, Fedarko NS: Flexible structures of SIBLING proteins, bone sialoprotein, and osteopontin. Biochem Biophys Res Commun 2001;280:460–465.
41.
Hoyer JR, Asplin JR, Otvos L Jr: Phosphorylated osteopontin peptides suppress crystallization by inhibiting the growth of calcium oxalate crystals. Kidney Int 2001;60:77–82.
42.
Worcester EM, Kleinman JG, Beshensky AM: Osteopontin production by cultured kidney cells. Ann NY Acad Sci 1995;760:266–278.
43.
Ljunghall S: Family history of renal stones in a population study of stone-formers and health subjects. Br J Urol 1979;51:249–252.
44.
Cailhier JF, Petrucci M, Valiquette L, Guay G, Ouimet D, Bonnardeaux A: Exclusion mapping of major crystallization inhibitors in idiopathic calcium urolithiasis. J Urol 2001;166:1484–1486.
45.
Yamate T, Tsuji H, Amasaki N, Iguchi M, Kurita T, Kohri K: Analysis of osteopontin DNA in patients with urolithiasis. Urol Res 2000;28:159–166.
46.
Yasui T, Fujita K, Hayashi Y, Ueda K, Kon S, Maeda M, Uede T, Kohri K: Quantification of osteopontin in the urine of healthy and stone-forming men. Urol Res 1999;27:225–230.
© 2004 S. Karger AG, Basel
2004
Copyright / Drug Dosage / Disclaimer
Copyright: 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.
You do not currently have access to this content.