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MEPE’s Diverse Effects on Mineralization

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Abstract

Matrix extracellular phosphoglycoprotein (MEPE) is an inhibitor of mineralization in situ and in cell cultures where altered expression is associated with oncogenic osteomalacia and hypophosphatemic rickets. The purpose of this study was to determine whether the intact protein or the peptide(s) originating from this protein was responsible for the inhibition. The ability of the intact protein and the acidic, serine- and aspartate-rich MEPE-associated motif (ASARM) peptide to promote or inhibit de novo hydroxyapatite formation and growth of hydroxyapatite seed crystals, in both phosphorylated and dephosphorylated forms, was assessed at room temperature in a dynamic gel diffusion system at 3.5 and 5 days. The most effective nucleator concentration was also examined when associated with fibrillar type I collagen. The phosphorylated intact protein was an effective promoter of mineralization in the gelatin gel diffusion system, while the ASARM peptide was an effective inhibitor. When dephosphorylated both the intact protein and the ASARM peptide had no effect on mineralization. Associated with collagen fibrils, some of the effect of the intact protein was lost. This study demonstrates the importance of posttranslational modification for the site-specific activity of MEPE and its ASARM peptide.

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References

  1. Rowe PS, de Zoysa PA, Dong R, Wang HR, White KE, Econs MJ, Oudet CL (2000) MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia. Genomics 67:54–68. doi:10.1006/geno.2000.6235

    Article  CAS  PubMed  Google Scholar 

  2. Argiro L, Desbarats M, Glorieux FH, Ecarot B (2001) Mepe, the gene encoding a tumor-secreted protein in oncogenic hypophosphatemic osteomalacia, is expressed in bone. Genomics 74:342–351. doi:10.1006/geno.2001.6553

    Article  CAS  PubMed  Google Scholar 

  3. Huq NL, Cross KJ, Ung M, Reynolds EC (2005) A review of protein structure and gene organisation for proteins associated with mineralised tissue and calcium phosphate stabilisation encoded on human chromosome 4. Arch Oral Biol 50:599–609. doi:10.1016/j.archoralbio.2004.12.009

    Article  CAS  PubMed  Google Scholar 

  4. Nampei A, Hashimoto J, Hayashida K, Tsuboi H, Shi K, Tsuji I, Miyashita H, Yamada T, Matsukawa N, Matsumoto M, Morimoto S, Ogihara T, Ochi T, Yoshikawa H (2004) Matrix extracellular phosphoglycoprotein (MEPE) is highly expressed in osteocytes in human bone. J Bone Miner Metab 22:176–184. doi:10.1007/s00774-003-0468-9

    Article  CAS  PubMed  Google Scholar 

  5. Gowen LC, Petersen DN, Mansolf AL, Qi H, Stock JL, Tkalcevic GT, Simmons HA, Crawford DT, Chidsey-Frink KL, Ke HZ, McNeish JD, Brown TA (2003) Targeted disruption of the osteoblast/osteocyte factor 45 gene (OF45) results in increased bone formation and bone mass. J Biol Chem 278:1998–2007. doi:10.1074/jbc.M203250200

    Article  CAS  PubMed  Google Scholar 

  6. Martin A, David V, Laurence JS, Schwarz PM, Lafer EM, Hedge AM, Rowe PS (2008) Degradation of MEPE, DMP1, and release of SIBLING ASARM-peptides (minhibins): ASARM-peptide(s) are directly responsible for defective mineralization in HYP. Endocrinology 149:1757–1772. doi:10.1210/en.2007-1205

    Article  CAS  PubMed  Google Scholar 

  7. Rowe PS, Kumagai Y, Gutierrez G, Garrett IR, Blacher R, Rosen D, Cundy J, Navvab S, Chen D, Drezner MK, Quarles LD, Mundy GR (2004) MEPE has the properties of an osteoblastic phosphatonin and minhibin. Bone 34:303–319. doi:10.1016/j.bone.2003.10.005

    Article  CAS  PubMed  Google Scholar 

  8. Addison WN, Nakano Y, Loisel T, Crine P, McKee MD (2008) MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM. J Bone Miner Res 23:1638–1649. doi:10.1359/jbmr.080601

    Article  CAS  PubMed  Google Scholar 

  9. Rowe PS, Garrett IR, Schwarz PM, Carnes DL, Lafer EM, Mundy GR, Gutierrez GE (2005) Surface plasmon resonance (SPR) confirms that MEPE binds to PHEX via the MEPE-ASARM motif: a model for impaired mineralization in X-linked rickets (HYP). Bone 36:33–46. doi:10.1016/j.bone.2004.09.015

    Article  CAS  PubMed  Google Scholar 

  10. Guo R, Rowe PS, Liu S, Simpson LG, Xiao ZS, Quarles LD (2002) Inhibition of MEPE cleavage by Phex. Biochem Biophys Res Commun 297:38–45

    Article  CAS  PubMed  Google Scholar 

  11. Silverman L, Boskey AL (2004) Diffusion systems for evaluation of biomineralization. Calcif Tissue Int 75:494–501. doi:10.1007/s00223-004-0019-y

    Article  CAS  PubMed  Google Scholar 

  12. Willis JB (1980) Determination of metals in blood serum by atomic absorption spectroscopy. I. Calcium. Spectrochim Acta 16:259–272

    Article  Google Scholar 

  13. Heinonen JK, Lahti RJ (1981) A new and convenient colorimetric determination of inorganic orthophosphate and its application to the assay of inorganic pyrophosphates. Anal Biochem 113:313–317

    Article  CAS  PubMed  Google Scholar 

  14. Sprowson AP, McCaskie AW, Birch MA (2008) ASARM-truncated MEPE and AC-100 enhance osteogenesis by promoting osteoprogenitor adhesion. J Orthop Res 26:1256–1262. doi:10.1002/jor.20606

    Article  CAS  PubMed  Google Scholar 

  15. Hayashibara T, Hiraga T, Yi B, Nomizu M, Kumagai Y, Nishimura R, Yoneda T (2004) A synthetic peptide fragment of human MEPE stimulates new bone formation in vitro and in vivo. J Bone Miner Res 19:455–462. doi:10.1359/JBMR.0301263

    Article  CAS  PubMed  Google Scholar 

  16. Six N, Septier D, Chaussain-Miller C, Blacher R, DenBesten P, Goldberg M (2007) Dentonin, a MEPE fragment, initiates pulp-healing response to injury. J Dent Res 86:780–785

    Article  CAS  PubMed  Google Scholar 

  17. Liu H, Li W, Shi S, Habelitz S, Gao C, Denbesten P (2005) MEPE is downregulated as dental pulp stem cells differentiate. Arch Oral Biol 50:923–928. doi:10.1016/j.archoralbio.2005.03.003

    Article  CAS  PubMed  Google Scholar 

  18. Siggelkow H, Schmidt E, Hennies B, Hüfner M (2004) Evidence of downregulation of matrix extracellular phosphoglycoprotein during terminal differentiation in human osteoblasts. Bone 35:570–576. doi:10.1016/j.bone.2004.03.033

    Article  CAS  PubMed  Google Scholar 

  19. Baht GS, Hunter GK, Goldberg HA (2008) Bone sialoprotein–collagen interaction promotes hydroxyapatite nucleation. Matrix Biol 27:600–608. doi:10.1016/j.matbio.2008.06.004

    Article  CAS  PubMed  Google Scholar 

  20. David V, Martin A, Hedge A-M, Rowe PSN (2009) MEPE is a new bone renal hormone and vascularization modulator. Endocrinology 150:4012–4023. doi:10.1210/en.2009-0216

    Article  CAS  PubMed  Google Scholar 

  21. Qin C, Baba O, Butler WT (2004) Post-translational modifications of sibling proteins and their roles in osteogenesis and dentinogenesis. Crit Rev Oral Biol Med 15:126–136

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  23. Gericke A, Qin C, Spevak L, Fujimoto Y, Butler WT, Sørensen ES, Boskey A (2005) Importance of phosphorylation for osteopontin regulation of biomineralization. Calcif Tissue Int 77:45–54. doi:10.1007/s00223-004-1288-1

    Article  CAS  PubMed  Google Scholar 

  24. Tartaix PH, Doulaverakis M, George A, Fisher LW, Butler WT, Qin C, Salih E, Tan M, Fujimoto Y, Spevak L, Boskey AL (2004) In vitro effects of dentin matrix protein-1 on hydroxyapatite formation provide insights into in vivo functions. J Biol Chem 279:18115–18120. doi:10.1074/jbc.M314114200

    Article  CAS  PubMed  Google Scholar 

  25. Gajjeraman S, Narayanan K, Hao J, Qin C, George A (2007) Matrix macromolecules in hard tissues control the nucleation and hierarchical assembly of hydroxyapatite. J Biol Chem 282:1193–1204. doi:10.1074/jbc.M604732200

    Article  CAS  PubMed  Google Scholar 

  26. Boskey AL, Maresca M, Doty S, Sabsay B, Veis A (1990) Concentration-dependent effects of dentin phosphophoryn in the regulation of in vitro hydroxyapatite formation and growth. Bone Miner 11:55–65

    Article  CAS  PubMed  Google Scholar 

  27. He G, Ramachandran A, Dahl T, George S, Schultz D, Cookson D, Veis A, George A (2005) Phosphorylation of phosphophoryn is crucial for its function as a mediator of biomineralization. J Biol Chem 280:33109–33114. doi:10.1074/jbc.M500159200

    Article  CAS  PubMed  Google Scholar 

  28. Boskey A, Spevak L, Tan M, Doty SB, Butler WT (2000) Dentin sialoprotein (DSP) has limited effects on in vitro apatite formation and growth. Calcif Tissue Int 67:472–478

    Article  CAS  PubMed  Google Scholar 

  29. Hunter GK, Goldberg HA (1993) Nucleation of hydroxyapatite by bone sialoprotein. Proc Natl Acad Sci USA 90:8562–8565

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by NIH grants DE04141 (to A. L. B.) and AR51598-01 (to P. S. N. R.). The authors express their thanks to all the students from Columbia University School of Dentistry who worked on this study over the past few years.

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Authors and Affiliations

  1. Musculoskeletal Integrity Program, Hospital for Special Surgery, 535 East 70th Street, New York, NY, 10021, USA

    Adele L. Boskey, Phyllis Chiang, Alexis Fermanis, Jared Brown & Hayat Taleb

  2. The Kidney Institute, Kansas University Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA

    Valentin David & Peter S. N. Rowe

Authors
  1. Adele L. Boskey
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  2. Phyllis Chiang
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  3. Alexis Fermanis
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  4. Jared Brown
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  5. Hayat Taleb
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  6. Valentin David
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  7. Peter S. N. Rowe
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Correspondence to Adele L. Boskey.

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The authors have stated that they have no conflicts of interest.

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Boskey, A.L., Chiang, P., Fermanis, A. et al. MEPE’s Diverse Effects on Mineralization. Calcif Tissue Int 86, 42–46 (2010). https://doi.org/10.1007/s00223-009-9313-z

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  • DOI: https://doi.org/10.1007/s00223-009-9313-z

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