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Importance of Phosphorylation for Osteopontin Regulation of Biomineralization

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Abstract

Previous in vitro and in vivo studies demonstrated that osteopontin (OPN) is an inhibitor of the formation and growth of hydroxyapatite (HA) and other biominerals. The present study tests the hypotheses that the interaction of OPN with HA is determined by the extent of protein phosphorylation and that this interaction regulates the mineralization process. Bone OPN as previously reported inhibited HA formation and HA-seeded growth in a gelatin-gel system. A transglutaminase-linked OPN polymer had similar effects. Recombinant, nonphosphorylated OPN and chemically dephosphorylated OPN, had no effect on HA formation or growth in this system. In contrast, highly phosphorylated milk OPN (mOPN) promoted HA formation. The mOPN stabilized the conversion of amorphous calcium phosphate (a noncrystalline constituent of milk) to HA, whereas bone OPN had a lesser effect on this conversion. Mixtures of OPN and osteocalcin known to form a complex in vitro, unexpectedly promoted HA formation. To test the hypothesis that small alterations in protein conformation caused by phosphorylation account for the differences in the observed ability of OPN to interact with HA, the conformation of bone OPN and mOPN in the presence and absence of crystalline HA was determined by attenuated total reflection (ATR) infrared (IR) spectroscopy. Both proteins exhibited a predominantly random coil structure, which was unaffected by the addition of Ca2+. Binding to HA did not alter the secondary structure of bone OPN, but induced a small increase of β-sheet (few percent) in mOPN. These data taken together suggest that the phosphorylation of OPN is an important factor in regulating the OPN-mediated mineralization process.

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References

  1. D Denhardt M Noda (1998) ArticleTitleOsteopontin expression and function: role in bone remodeling J Cell Biochem 30-31 92–102 Occurrence Handle10.1002/(SICI)1097-4644(1998)72:30/31+<92::AID-JCB13>3.0.CO;2-A

    Article  Google Scholar 

  2. CM Giachelli S Steitz (2000) ArticleTitleOsteopontin: a versatile regulator of inflammation and biomineralization Matrix Biol 19 615–622 Occurrence Handle10.1016/S0945-053X(00)00108-6 Occurrence Handle11102750

    Article  PubMed  Google Scholar 

  3. J Gokhale PG Robey AL Boskey (2001) The Biochemistry of bone R Marcus D Feldman J Kelsey (Eds) Osteoporosis, Second Edition vol 1 Academic Press San Diego 107–189

    Google Scholar 

  4. J Sodek B Ganss MD McKee (2000) ArticleTitleOsteopontin Crit Rev Oral Biol Med 11 279–303 Occurrence Handle11021631

    PubMed  Google Scholar 

  5. MS Fernandez C Escobar I Lavelin M Pines JL Arias (2003) ArticleTitleLocalization of osteopontin in oviduct tissue and eggshell during different stages of the avian egg laying cycle J Struct Biol 143 171–180 Occurrence Handle10.1016/j.jsb.2003.08.007 Occurrence Handle14572472

    Article  PubMed  Google Scholar 

  6. A Oldberg A Franzen D Heinegard (1986) ArticleTitleCloning and sequence analysis of rat bone sialoprotein (osteopontin) cDNA reveals an Arg-Gly-Asp cell-binding sequence Proc Natl Acad Sci USA 83 8819–8823 Occurrence Handle3024151

    PubMed  Google Scholar 

  7. CW Prince T Oosawa WT Butler M Tomana AS Bhown M Bhown RE Schrohenloher (1987) ArticleTitleIsolation, characterization, and biosynthesis of a phosphorylated glycoprotein from rat bone J Biol Chem 262 2900–2907 Occurrence Handle3469201

    PubMed  Google Scholar 

  8. WT Butler (1995) ArticleTitleStructural and functional domains of osteopontin Ann N Y Acad Sci 760 6–11 Occurrence Handle7785926

    PubMed  Google Scholar 

  9. PL Chang CW Prince (1994) ArticleTitle1 Alpha, 25-dihydroxyvitamin D3 stimulates synthesis and secretion of nonphosphorylated osteopontin (secreted phosphoprotein 1) in mouse JB6 epidermal cells Cancer Res 51 2144–2150

    Google Scholar 

  10. M Noda RL Vogel AM Craig J Prahl HF DeLuca DT Denhardt (1990) ArticleTitleIdentification of a DNA sequence responsible for binding of the 1,25-dihydroxyvitamin D3 receptor and 1,25-dihydroxyvitamin D3 enhancement of mouse secreted phosphoprotein 1 (SPP-1 or osteopontin) gene expression Proc Natl Acad Sci USA 87 9995–9999 Occurrence Handle2175918

    PubMed  Google Scholar 

  11. GR Beck SuffixJr B Zerler E Moran (2000) ArticleTitlePhosphate is a specific signal for induction of osteopontin gene expression Proc Natl Acad Sci USA 97 8352–8357 Occurrence Handle10.1073/pnas.140021997 Occurrence Handle10890885

    Article  PubMed  Google Scholar 

  12. M Noda GA Rodan (1989) ArticleTitleTranscriptional regulation of osteopontin production in rat osteoblast-like cells by parathyroid hormone J Biol Chem 108 713–718

    Google Scholar 

  13. CW Prince D Dickie CL Krumdieck (1991) ArticleTitleOsteopontin, a substrate for transglutaminase and factor XIII activity Biochem Biophys Res Commun 177 1205–1210 Occurrence Handle10.1016/0006-291X(91)90669-X Occurrence Handle1676261

    Article  PubMed  Google Scholar 

  14. ES Sørensen LK Rasmussen L Møller PH Jensen P Hørup TE Petersen (1994) ArticleTitleLocalization of transglutaminase-reactive glutamine residues in bovine osteopontin J Biochem 304 13–16

    Google Scholar 

  15. MT Kaartinen A Pirhonen A Linnala-Kankkunen PH Mäenpää (1997) ArticleTitleTransglutaminase-catalyzed cross-linking of osteopontin is inhibited by osteocalcin J Biol Chem 272 22736–22741 Occurrence Handle10.1074/jbc.272.36.22736 Occurrence Handle9278432

    Article  PubMed  Google Scholar 

  16. MT Kaartinen A Pirhonen A Linnala-Kankkunen PH Mäenpää (1999) ArticleTitleTransglutaminase treated osteopontin exhibits increased collagen binding properties Biol Chem 274 1729–1735 Occurrence Handle10.1074/jbc.274.3.1729

    Article  Google Scholar 

  17. MT Kaartinen S El-Maadawy NH Räsänen MD McKee (2002) ArticleTitleTransglutaminase and its substrates in bone J Bone Miner Res 12 2161–2173

    Google Scholar 

  18. S Ikeda A Nomura T Yamaguchi T Suda S Yoshiki (1992) ArticleTitleIn situ hybridization of bone matrix proteins in undecalcified adult rat bone sections J Histochem Cytochem 40 1079–1088 Occurrence Handle1619274

    PubMed  Google Scholar 

  19. CW Prince WT Butler (1987) ArticleTitle1,25-Dihydroxyvitamin D3 regulates the biosynthesis of osteopontin, a bone-derived cell attachment protein, in clonal osteoblast-like osteosarcoma cells Collagen Rel Res 7 305–313

    Google Scholar 

  20. T Yamate H Mocharla Y Taguchi JU Igietseme SC Manoiagas E Abe (1997) ArticleTitleOsteopontin expression by osteoclast and osteoblast progenitors in the murine bone marrow: demonstration of its requirement for osteoclastogenesis and its increase after ovariectomy Endocrinology 138 3047–3055 Occurrence Handle10.1210/en.138.7.3047 Occurrence Handle9202251

    Article  PubMed  Google Scholar 

  21. M Ishijima SR Rittling T Yamashita K Tsuji H Kurosawa A Nifuji DT Denhardt M Noda (2001) ArticleTitleEnhancement of osteoclastic bone resorption and suppression of osteoblastic bone formation in response to reduced mechanical stress do not occur in the absence of osteopontin J Exp Med 193 399–404 Occurrence Handle10.1084/jem.193.3.399 Occurrence Handle11157060

    Article  PubMed  Google Scholar 

  22. H Ihara DT Denhardt K Furuya T Yamashita Y Muguruma K Tsuji KA Hruska K Higashio S Enomoto A Nifuji SR Rittling M Noda (2001) ArticleTitleParathyroid hormone-induced bone resorption does not occur in the absence of osteopontin J Biol Chem 276 13065–13071 Occurrence Handle10.1074/jbc.M010938200 Occurrence Handle11278791

    Article  PubMed  Google Scholar 

  23. SR Rittling HN Matsumoto MD McKee A Nanci XR An KE Novick AJ Kowalski M Noda DT Denhardt (1998) ArticleTitleMice lacking osteopontin show normal development and bone structure but display altered osteoclast formation in vitro J Bone Miner Res 13 1101–1111 Occurrence Handle9661074

    PubMed  Google Scholar 

  24. H Yoshitake SR Rittling DT Denhardt M Noda (1999) ArticleTitleOsteopontin-deficient mice are resistant to ovariectomy-induced bone resorption Proc Natl Acad Sci USA 97 8156–8160 Occurrence Handle10.1073/pnas.96.14.8156

    Article  Google Scholar 

  25. AL Boskey L Spevak E Paschalis SB Doty MD McKee (2002) ArticleTitleOsteopontin deficiency increases mineral content and mineral crystallinity in mouse bone Calcif Tissue Int 71 145–154 Occurrence Handle10.1007/s00223-001-1121-z Occurrence Handle12073157

    Article  PubMed  Google Scholar 

  26. SR Qiu A Wierzbicki CA Orme AM Cody JR Hoyer GH Nancollas S Zepeda JJ Yoreo ParticleDe (2004) ArticleTitleMolecular modulation of calcium oxalate crystallization by osteopontin and citrate Proc Natl Acad Sci USA 101 1811–1815 Occurrence Handle10.1073/pnas.0307900100 Occurrence Handle14766970

    Article  PubMed  Google Scholar 

  27. MT Hincke M St. Maurice (2000) Phosphorylation-dependent modulation of calcium carbonate precipitation by chicken eggshell matrix proteins M Goldberg A Boskey C Robinson (Eds) Chemistry and Biology of Mineralized Tissues, Am Acad Orthop Surg Rosemont IL 13–17

    Google Scholar 

  28. Y Asou SR Rittling H Yoshitake K Tsuji K Shinomiya A Nifuji DT Denhardt M Noda (2001) ArticleTitleOsteopontin facilitates angiogenesis, accumulation of osteoclasts, and resorption in ectopic bone Endocrinology 142 1325–1332 Occurrence Handle10.1210/en.142.3.1325 Occurrence Handle11181551

    Article  PubMed  Google Scholar 

  29. T Wada MD McKee S Steitz CM Giachelli (1999) ArticleTitleCalcification of vascular smooth muscle cell cultures: inhibition by osteopontin Circ Res 35 166–178

    Google Scholar 

  30. PJ Neame WT Butler (1996) ArticleTitlePosttranslational modification in rat bone osteopontin Connect Tissue Res 35 145–150 Occurrence Handle9084652

    PubMed  Google Scholar 

  31. E Salih J Wang J Mah R Fluckiger (2002) ArticleTitleNatural variation in the extent of phosphorylation of bone phosphoproteins as a function of in vivo new bone formation induced by demineralized bone matrix in soft tissue and bony environments Biochem J 364 465–474 Occurrence Handle10.1042/BJ20011272 Occurrence Handle12023890

    Article  PubMed  Google Scholar 

  32. C Qin O Baba WT Butler (2004) ArticleTitlePost-translational modifications of sibling proteins and their roles in osteogenesis and dentinogenesis Crit Rev Oral Biol Med 15 126–136 Occurrence Handle15187031

    PubMed  Google Scholar 

  33. JB Safran WT Butler MC Farach-Carson (1998) ArticleTitleModulation of osteopontin post-translational state by 1, 25-(OH)2-vitamin D3 Dependence on Ca2+ influx J Biol Chem 273 29935–29941 Occurrence Handle10.1074/jbc.273.45.29935 Occurrence Handle9792712

    Article  PubMed  Google Scholar 

  34. Y Fujusawa S Kuboki S Sasaki (1986) ArticleTitleChanges in interaction of bovine dentin phosphophory with calcium and hydroxyapatite by chemical modification Calcif Tissue Int 39 248–251 Occurrence Handle3024782

    PubMed  Google Scholar 

  35. AL Boskey M Maresca W Ullrich SB Doty WT Butler CW Prince (1993) ArticleTitleOsteopontin-hydroxyapatite interactions in vitro: inhibition of hydroxyapatite formation and growth in a gelatin-gel Bone Miner 22 147–159 Occurrence Handle8251766

    PubMed  Google Scholar 

  36. GK Hunter CL Kyle HA Goldberg (1994) ArticleTitleModulation of crystal formation by bone phosphoproteins: structural specificity of the osteopontin-mediated inhibition of hydroxyapatite formation Biochem J 300 723–728 Occurrence Handle8010953

    PubMed  Google Scholar 

  37. A Endo MJ Glimcher (1989) ArticleTitleThe effect of complexing phosphoproteins to decalcified collagen on in vitro calcification Connect Tissue Res 21 179–190 Occurrence Handle2605942

    PubMed  Google Scholar 

  38. AL Boskey SB Doty I Binderman (1994) ArticleTitleAdenosine 5-triphosphate promotes mineralization in differentiating chick limb-bud mesenchymal cell cultures Microsc Res Tech 28 492–504 Occurrence Handle10.1002/jemt.1070280605 Occurrence Handle7949395

    Article  PubMed  Google Scholar 

  39. GF Weber S Zawaideh S Hikita VA Kumar H Cantor S Ashkar (2002) ArticleTitlePhosphorylation-dependent interaction of osteopontin with its receptors regulates macrophage migration and activation J Leukoc Biol 72 752–764 Occurrence Handle12377945

    PubMed  Google Scholar 

  40. S Razzouk JC Brunn C Qin CE Tye HA Goldberg WT Butler (2002) ArticleTitleOsteopontin posttranslational modifications, possibly phosphorylation, are required for in vitro bone resorption but not osteoclast adhesion Bone 30 40–47 Occurrence Handle10.1016/S8756-3282(01)00637-8 Occurrence Handle11792563

    Article  PubMed  Google Scholar 

  41. L Addadi S Weiner M Geva (2001) ArticleTitleOn how proteins, interact with crystals and their effect on crystal formation Z Kardiol 90 Suppl 3 92–98

    Google Scholar 

  42. S Winkler D Wilson DL Kaplan (2000) ArticleTitleControlling beta-sheet assembly in genetically engineereds silk by enzymatic phosphorylation/dephosphorylation Biochemistry 39 12739–12746 Occurrence Handle10.1021/bi001335w Occurrence Handle11027155

    Article  PubMed  Google Scholar 

  43. C Qin JC Brunn J Jones A George A Ramachandran JP Gorski WT Butler (2001) ArticleTitleA comparative study of sialic acid-rich proteins in rat bone and dentin Eur J Oral Sci 109 133–141 Occurrence Handle10.1034/j.1600-0722.2001.00001.x Occurrence Handle11347657

    Article  PubMed  Google Scholar 

  44. ES Sorensen P Hojrup TE Petersen (1995) ArticleTitlePosttranslational modifications of bovine osteopontin: identification of twenty-eight phosphorylation and three O-glycosylation sites Protein Sci4 2040–2049

    Google Scholar 

  45. K Jonsson D McDevitt MH McGavin JM Patti M Hook (1995) ArticleTitleStaphylococcus aureus expresses a major histocompatibility complex class II analog J Biol Chem 270 21457–21460 Occurrence Handle10.1074/jbc.270.37.21457 Occurrence Handle7545162

    Article  PubMed  Google Scholar 

  46. AA Baykov OA Evtushenko SM Avaeva (1988) ArticleTitleA malachite green procedure for orthophosphate determination and, its use in alkaline phosphatase-based enzyme immunoassay Anal Biochem 171 266–270 Occurrence Handle10.1016/0003-2697(88)90484-8 Occurrence Handle3044186

    Article  PubMed  Google Scholar 

  47. CM Gundberg PV Hauschka JB Lian PM Gallop (1984) ArticleTitleOsteocalcin: isolation, characterization, and detection Methods Enzymol 107 516–544 Occurrence Handle6094965

    PubMed  Google Scholar 

  48. AL Boskey (1989) ArticleTitleHydroxyapatite formation in a dynamic gelatin gel system J Phys Chem 94 1628–1633 Occurrence Handle10.1021/j100341a086

    Article  Google Scholar 

  49. L Silverman AL Boskey (2004) ArticleTitleDiffusion systems for evaluation of biomineralization Calcif Tissue Int 75 494–501 Occurrence Handle10.1007/s00223-004-0019-y Occurrence Handle15455184

    Article  PubMed  Google Scholar 

  50. NC Blumenthal F Betts AS Posner (1975) ArticleTitleEffect of carbonate and biological macromolecules on formation and properties of hydroxyapatite Calcif Tissue Res 18 81–90 Occurrence Handle1148899

    PubMed  Google Scholar 

  51. JB Willis (1960) ArticleTitleDetermination of metals in blood serum by atomic absorption spectroscopy I. Calcium. Spectrocbim Acta 16 259–272

    Google Scholar 

  52. JK Heinonen RJ Lahti (1981) ArticleTitleA new and convenient colorimetric determination of inorganic orthophosphate and its application to the assay of inorganic pyrophosphates Anal Biochem 113 313–317 Occurrence Handle10.1016/0003-2697(81)90082-8 Occurrence Handle6116463

    Article  PubMed  Google Scholar 

  53. AL Boskey AS Posner (1973) ArticleTitleConversion of amorphous calcium phosphate to microcrystalline hydroxyapatite. A pH-dependent solution-mediated, solid-state conversion J Phys Chem 77 2313–2317 Occurrence Handle10.1021/j100638a011

    Article  Google Scholar 

  54. M Diem (1993) Introduction to modern vibrational spectroscopy Wiley New York

    Google Scholar 

  55. AL Boskey (1995) ArticleTitleOsteopontin and related phosphorylated sialoproteins: effects on mineralization Ann NY Acad Sci 760 249–256 Occurrence Handle7785899

    PubMed  Google Scholar 

  56. HA Goldberg KJ Warner MC Li GK Hunter (2001) ArticleTitleBinding of bone sialoprotein, osteopontin and synthetic polypeptides to hydroxyapatite Connect Tissue Res 42 25–37 Occurrence Handle11696986

    PubMed  Google Scholar 

  57. TC McGann RD Kearney W Buchheim AS Posner F Betts NC Blumenthal (1983) ArticleTitleAmorphous calcium phosphate in casein micelles of bovine milk Calcif Tissue Int 35 821–823 Occurrence Handle6652558

    PubMed  Google Scholar 

  58. NM Ritter MC Farach-Carson WT Butler (1992) ArticleTitleEvidence for the formation of a complex between osteopontin and osteocalcin J Bone Miner Res 7 877–885 Occurrence Handle1442202

    PubMed  Google Scholar 

  59. LW Fisher DA Torchia B Fohr MF Young NS Fedarko (2001) ArticleTitleFlexible structures of SIBLING proteins, bone sialoprotein, and osteopontin Biochem Biophys Res Commun 280 460–465 Occurrence Handle10.1006/bbrc.2000.4146 Occurrence Handle11162539

    Article  PubMed  Google Scholar 

  60. JLR Arrondo FM Goni (1999) ArticleTitleStructure and dynamics of membrane proteins as studied by infrared spectroscopy Prog Biophys Mol Biol 72 367–405 Occurrence Handle10.1016/S0079-6107(99)00007-3 Occurrence Handle10605294

    Article  PubMed  Google Scholar 

  61. PI Haris D Chapman (1996) Fourier transform infrared spectroscopic studies of biomembrane systems HH Mantsch D Chapman (Eds) Infrared spectroscopy of biomolecules Wiley New York 239–279

    Google Scholar 

  62. AR Hayman TM Cox (2003) ArticleTitleTartrate-resistant acid phosphatase knockout mice J Bone Miner Res 18 1905–1907 Occurrence Handle14584904

    PubMed  Google Scholar 

  63. DA Pampena KA Robertson O Litvinova G Lajoie HA Goldberg GK Hunter (2004) ArticleTitleInhibition of hydroxyapatite formation by osteopontin phosphopeptides Biochem J 378 1083–1087 Occurrence Handle10.1042/BJ20031150 Occurrence Handle14678013

    Article  PubMed  Google Scholar 

  64. S Ito T Saito K Amano (2004) ArticleTitleIn vitro apatite induction by osteopontin: interfacial energy for hydroxyapatite nucleation on osteopontin J Biomed Mater Res 69A 11–16 Occurrence Handle10.1002/jbm.a.20066

    Article  Google Scholar 

  65. SA Steitz MY Speer MD McKee L Liaw M Almedia H Yang CM Giachelli (2002) ArticleTitleOsteopontin inhibits mineral deposition and promotes regression of ectopic calcification Am J Pathol 161 2035–2046 Occurrence Handle12466120

    PubMed  Google Scholar 

  66. S Jono C Peinado CM Giachelli (2000) ArticleTitlePhosphorylation of osteopontin is required for inhibition of vascular smooth muscle cell calcification J Biol Chem 275 20197–20203 Occurrence Handle10.1074/jbc.M909174199 Occurrence Handle10766759

    Article  PubMed  Google Scholar 

  67. JP Gorski E Kremer J Ruiz-Perez GE Wise A Artigues (1995) ArticleTitleConformational analyses on soluble and surface bound osteopontin Ann N Y Acad Sci 760 12–23 Occurrence Handle7785891

    PubMed  Google Scholar 

  68. K Johnson J Goding D Etten ParticleVan A Sali SI Hu D Farley H Krug L Hessle JL Millan R Terkeltaub (2003) ArticleTitleLinked deficiencies in extracellular PP (i) and osteopontin mediate pathologic calcification associated with defective PC-1 and ANK expression J Bone Miner Res 18 994–1004 Occurrence Handle12817751

    PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank the members of their research laboratories for their assistance with this study. Support was provided by NIH grants DE04141 (ALB); DE05092 (WTB & CQ), and NSF CHE-0215970 (AG). The support of Arla Foods, the Danish Dairy Research Foundation, and the Danish Research and Development Programme for Food Technology is acknowledged (ESS).

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Authors and Affiliations

  1. Department of Chemistry, Kent State University, Kent, OH, USA

    A. Gericke

  2. Department of Endodontics and Peridontics, University of Texas Health Science Center at Houston, Dental Branch, Houston, TX, USA

    C. Qin & W. T. Butler

  3. Mineralized Tissues Laboratory, Research Division, Hospital for Special Surgery, New York, NY, USA

    L. Spevak, Y. Fujimoto & A. L. Boskey

  4. Protein Chemistry Laboratory, Department of Molecular Biology, University of Aarhus, Denmark

    E. S. Sørensen

  5. Department of Biochemistry, Weil Medical College of Cornell University and Program in Physiology, Biophysics, Systems Biology, Graduate School of Medical Sciences, New york, NY, USA

    A. L. Boskey

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  1. A. Gericke
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Gericke, A., Qin, C., Spevak, L. et al. Importance of Phosphorylation for Osteopontin Regulation of Biomineralization. Calcif Tissue Int 77, 45–54 (2005). https://doi.org/10.1007/s00223-004-1288-1

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