Journal of Bone and Mineral Metabolism

, Volume 30, Issue 1, pp 10–18 | Cite as

Can features of phosphate toxicity appear in normophosphatemia?

Invited Review

Abstract

Phosphate is an indispensable nutrient for the formation of nucleic acids and the cell membrane. Adequate phosphate balance is a prerequisite for basic cellular functions ranging from energy metabolism to cell signaling. More than 85% of body phosphate is present in the bones and teeth. The remaining phosphate is distributed in various soft tissues, including skeletal muscle. A tiny amount, around 1% of total body phosphate, is distributed both in the extracellular fluids and within the cells. Impaired phosphate balance can affect the functionality of almost all human systems, including muscular, skeletal, and vascular systems, leading to an increase in morbidity and mortality of the involved patients. Currently, measuring serum phosphate level is the gold standard to estimate the overall phosphate status of the body. Despite the biological and clinical significance of maintaining delicate phosphate balance, serum levels do not always reflect the amount of phosphate uptake and its distribution. This article briefly discusses the potential that some of the early consequences of phosphate toxicity might not be evident from serum phosphate levels.

Keywords

Klotho FGF23 Vitamin D Calcium 

Notes

Acknowledgements

Some of the original research that formed the basis of this review article was performed by Drs. Mutsuko Ohnishi (MD, PhD), Shigeko Kato, (PhD), Junko Akiyoshi, (MD), Kazuyoshi Uchihashi, (MD, PhD), Khadijah Turkistani (BDS), and Yonggeun Hong (PhD) of the Department of Oral Medicine, Infection and Immunity at the Harvard School of Dental Medicine, Boston, MA, USA, and supported by a grant (R01-DK077276 to M.S. Razzaque) from the National Institute of Diabetes and Digestive and Kidney Diseases.

Conflict of interest

None.

References

  1. 1.
    Slatopolsky E, Rutherford WE, Rosenbaum R, Martin K, Hruska K (1977) Hyperphosphatemia. Clin Nephrol 7:138–146PubMedGoogle Scholar
  2. 2.
    Gaasbeek A, Meinders AE (2005) Hypophosphatemia: an update on its etiology and treatment. Am J Med 118:1094–1101PubMedCrossRefGoogle Scholar
  3. 3.
    Razzaque MS (2009) The FGF23–klotho axis: endocrine regulation of phosphate homeostasis. Nat Rev Endocrinol 5:611–619PubMedCrossRefGoogle Scholar
  4. 4.
    Iotti S, Lodi R, Gottardi G, Zaniol P, Barbiroli B (1996) Inorganic phosphate is transported into mitochondria in the absence of ATP biosynthesis: an in vivo 31P NMR study in the human skeletal muscle. Biochem Biophys Res Commun 225:191–194PubMedCrossRefGoogle Scholar
  5. 5.
    Hutson SM, Williams GD, Berkich DA, LaNoue KF, Briggs RW (1992) A 31P NMR study of mitochondrial inorganic phosphate visibility: effects of Ca2+, Mn2+, and the pH gradient. Biochemistry 31:1322–1330PubMedCrossRefGoogle Scholar
  6. 6.
    Drezner M (2002) Phosphorus homeostasis and related disorders. In: Bilezikian J, Raisz L, Rodan G (eds) Principles in bone biology, 2nd edn. Academic Press, New York, pp 321–338CrossRefGoogle Scholar
  7. 7.
    Razzaque MS (2009) FGF23-mediated regulation of systemic phosphate homeostasis: is klotho an essential player? Am J Physiol Renal Physiol 296:F470–F476PubMedCrossRefGoogle Scholar
  8. 8.
    Econs MJ (1999) New insights into the pathogenesis of inherited phosphate wasting disorders. Bone (NY) 25:131–135CrossRefGoogle Scholar
  9. 9.
    Miyamoto K, Ito M, Segawa H, Kuwahata M (2003) Molecular targets of hyperphosphataemia in chronic renal failure. Nephrol Dial Transplant 18(suppl 3):iii79–iii80Google Scholar
  10. 10.
    Quarles LD (2003) FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization. Am J Physiol Endocrinol Metab 285:E1–E9PubMedGoogle Scholar
  11. 11.
    Marks J, Debnam ES, Unwin RJ (2010) Phosphate homeostasis and the renal–gastrointestinal axis. Am J Physiol Renal Physiol 299:F285–F296PubMedCrossRefGoogle Scholar
  12. 12.
    Hattenhauer O, Traebert M, Murer H, Biber J (1999) Regulation of small intestinal Na-Pi type IIb cotransporter by dietary phosphate intake. Am J Physiol Gastrointest Liver Physiol 277:G756–G762Google Scholar
  13. 13.
    Sabbagh Y, O’Brien SP, Song W, Boulanger JH, Stockmann A, Arbeeny C et al (2009) Intestinal Npt2b plays a major role in phosphate absorption and homeostasis. J Am Soc Nephrol 20:2348–2358PubMedCrossRefGoogle Scholar
  14. 14.
    Corut A, Senyigit A, Ugur SA, Altin S, Ozcelik U, Calisir H et al (2006) Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis. Am J Hum Genet 79:650–656PubMedCrossRefGoogle Scholar
  15. 15.
    Tenenhouse HS (2005) Regulation of phosphorus homeostasis by the type IIa Na/phosphate cotransporter. Annu Rev Nutr 25:197–214PubMedCrossRefGoogle Scholar
  16. 16.
    Murer H, Forster I, Hilfiker H, Pfister M, Kaissling B, Lotscher M et al (1998) Cellular/molecular control of renal Na/Pi-cotransport. Kidney Int Suppl 65:S2–S10PubMedCrossRefGoogle Scholar
  17. 17.
    Gattineni J, Bates C, Twombley K, Dwarakanath V, Robinson ML, Goetz R et al (2009) FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Renal Physiol 297:F282–F291PubMedCrossRefGoogle Scholar
  18. 18.
    Ohnishi M, Nakatani T, Lanske B, Razzaque MS (2009) In vivo genetic evidence for suppressing vascular and soft-tissue calcification through the reduction of serum phosphate levels, even in the presence of high serum calcium and 1,25-dihydroxyvitamin D levels. Circ Cardiovasc Genet 2:583–590PubMedCrossRefGoogle Scholar
  19. 19.
    Miyamoto K, Ito M, Kuwahata M, Kato S, Segawa H (2005) Inhibition of intestinal sodium-dependent inorganic phosphate transport by fibroblast growth factor 23. Ther Apher Dial 9:331–335PubMedCrossRefGoogle Scholar
  20. 20.
    Hu MC, Shi M, Zhang J, Pastor J, Nakatani T, Lanske B et al (2010) Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J 24:3438–3450PubMedCrossRefGoogle Scholar
  21. 21.
    Imel EA, Econs MJ (2005) Fibroblast growth factor 23: roles in health and disease. J Am Soc Nephrol 16:2565–2575PubMedCrossRefGoogle Scholar
  22. 22.
    Razzaque MS, Lanske B (2007) The emerging role of the fibroblast growth factor-23-klotho axis in renal regulation of phosphate homeostasis. J Endocrinol 194:1–10PubMedCrossRefGoogle Scholar
  23. 23.
    Quarles LD (2008) Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 118:3820–3828PubMedCrossRefGoogle Scholar
  24. 24.
    Razzaque MS (2009) Does FGF23 toxicity influence the outcome of chronic kidney disease? Nephrol Dial Transplant 24:4–7PubMedCrossRefGoogle Scholar
  25. 25.
    Fukagawa M, Hamada Y, Nakanishi S, Tanaka M (2006) The kidney and bone metabolism: nephrologists’ point of view. J Bone Miner Metab 24:434–438PubMedCrossRefGoogle Scholar
  26. 26.
    Kuro-o M (2010) Overview of the FGF23–klotho axis. Pediatr Nephrol 25:583–590PubMedCrossRefGoogle Scholar
  27. 27.
    Razzaque MS (2011) Osteo-renal regulation of systemic phosphate metabolism. IUBMB Life 63:240–247PubMedCrossRefGoogle Scholar
  28. 28.
    Nabeshima Y (2008) The discovery of alpha-klotho and FGF23 unveiled new insight into calcium and phosphate homeostasis. Cell Mol Life Sci 65:3218–3230PubMedCrossRefGoogle Scholar
  29. 29.
    Razzaque MS (2011) Phosphate toxicity: new insights into an old problem. Clin Sci (Lond) 120:91–97CrossRefGoogle Scholar
  30. 30.
    Juppner H (2011) Phosphate and FGF-23. Kidney Int 79(suppl 121):S24–S27Google Scholar
  31. 31.
    Yamashita T (2005) Structural and biochemical properties of fibroblast growth factor 23. Ther Apher Dial 9:313–318PubMedCrossRefGoogle Scholar
  32. 32.
    Eswarakumar VP, Lax I, Schlessinger J (2005) Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 16:139–149PubMedCrossRefGoogle Scholar
  33. 33.
    Mohammadi M, Olsen SK, Ibrahimi OA (2005) Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev 16:107–137PubMedCrossRefGoogle Scholar
  34. 34.
    Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP et al (2006) Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 281:6120–6123PubMedCrossRefGoogle Scholar
  35. 35.
    Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K et al (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature (Lond) 444:770–774CrossRefGoogle Scholar
  36. 36.
    Liu S, Vierthaler L, Tang W, Zhou J, Quarles LD (2008) FGFR3 and FGFR4 do not mediate renal effects of FGF23. J Am Soc Nephrol doi:10.1681/ASN.2007121301
  37. 37.
    Kuro-o M (2006) Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism. Curr Opin Nephrol Hypertens 15:437–441PubMedCrossRefGoogle Scholar
  38. 38.
    Medici D, Razzaque MS, Deluca S, Rector TL, Hou B, Kang K et al (2008) FGF-23-klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis. J Cell Biol 182:459–465PubMedCrossRefGoogle Scholar
  39. 39.
    Chen CD, Podvin S, Gillespie E, Leeman SE, Abraham CR (2007) Insulin stimulates the cleavage and release of the extracellular domain of klotho by ADAM10 and ADAM17. Proc Natl Acad Sci USA 104:19796–19801PubMedCrossRefGoogle Scholar
  40. 40.
    Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y (1998) Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun 242:626–630PubMedCrossRefGoogle Scholar
  41. 41.
    Nakatani T, Bara S, Ohnishi M, Densmore MJ, Taguchi T, Goetz R et al (2009) In vivo genetic evidence of klotho-dependent functions of FGF23 in regulation of systemic phosphate homeostasis. FASEB J 23:433–441PubMedCrossRefGoogle Scholar
  42. 42.
    Razzaque MS (2010) Therapeutic potential of klotho–FGF23 fusion polypeptides: WO2009095372. Expert Opin Ther Pat 20:981–985PubMedCrossRefGoogle Scholar
  43. 43.
    Nakatani T, Ohnishi M, Razzaque MS (2009) Inactivation of klotho function induces hyperphosphatemia even in presence of high serum fibroblast growth factor 23 levels in a genetically engineered hypophosphatemic (Hyp) mouse model. FASEB J 23:3702–3711PubMedCrossRefGoogle Scholar
  44. 44.
    Ichikawa S, Imel EA, Kreiter ML, Yu X, Mackenzie DS, Sorenson AH et al (2007) A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest 117:2684–2691PubMedCrossRefGoogle Scholar
  45. 45.
    Ohnishi M, Razzaque MS (2010) Dietary and genetic evidence for phosphate toxicity accelerating mammalian aging. FASEB J 24:3562–3571Google Scholar
  46. 46.
    ADHR Consortium (2000) Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. The ADHR Consortium. Nat Genet 26:345–348CrossRefGoogle Scholar
  47. 47.
    Gribaa M, Younes M, Bouyacoub Y, Korbaa W, Ben Charfeddine I, Touzi M et al (2010) An autosomal dominant hypophosphatemic rickets phenotype in a Tunisian family caused by a new FGF23 missense mutation. J Bone Miner Metab 28:111–115PubMedCrossRefGoogle Scholar
  48. 48.
    Ohnishi M, Nakatani T, Lanske B, Razzaque MS (2009) Reversal of mineral ion homeostasis and soft-tissue calcification of klotho knockout mice by deletion of vitamin D1 alpha-hydroxylase. Kidney Int 75:1166–1172PubMedCrossRefGoogle Scholar
  49. 49.
    Imanishi Y, Hashimoto J, Ando W, Kobayashi K, Ueda T, Nagata Y, et al (2011) Matrix extracellular phosphoglycoprotein is expressed in causative tumors of oncogenic osteomalacia. J Bone Miner Metab doi:10.1007/s00774-011-0290-8
  50. 50.
    Kitaoka T, Namba N, Miura K, Kubota T, Ohata Y, Fujiwara M et al (2011) Decrease in serum FGF23 levels after intravenous infusion of pamidronate in patients with osteogenesis imperfecta. J Bone Miner Metab 29:598–605PubMedCrossRefGoogle Scholar
  51. 51.
    Benet-Pages A, Orlik P, Strom TM, Lorenz-Depiereux B (2005) An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum Mol Genet 14:385–390PubMedCrossRefGoogle Scholar
  52. 52.
    Sun Y, Wang O, Xia W, Jiang Y, Li M, Xing X et al (2011) FGF23 analysis of a Chinese family with autosomal dominant hypophosphatemic rickets. J Bone Miner Metab. doi:10.1007/s00774-011-0285-5
  53. 53.
    Bai X, Miao D, Li J, Goltzman D, Karaplis AC (2004) Transgenic mice overexpressing human fibroblast growth factor 23(R176Q) delineate a putative role for parathyroid hormone in renal phosphate wasting disorders. Endocrinology 145:5269–5279PubMedCrossRefGoogle Scholar
  54. 54.
    Sitara D, Razzaque MS, Hesse M, Yoganathan S, Taguchi T, Erben RG et al (2004) Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 23:421–432PubMedCrossRefGoogle Scholar
  55. 55.
    DeLuca S, Sitara D, Kang K, Marsell R, Jonsson K, Taguchi T et al (2008) Amelioration of the premature aging-like features of Fgf-23 knockout mice by genetically restoring the systemic actions of FGF-23. J Pathol 216:345–355PubMedCrossRefGoogle Scholar
  56. 56.
    Razzaque MS (2007) Does renal ageing affect survival? Ageing Res Rev 6:211–222PubMedCrossRefGoogle Scholar
  57. 57.
    Taguchi T, Nazneen A, Al-Shihri AA, Turkistani KA, Razzaque MS (2011) Heat shock protein 47: a novel biomarker of phenotypically altered collagen-producing cells. Acta Histochem Cytochem 44:35–41Google Scholar
  58. 58.
    Razzaque MS, Taguchi T (2002) Cellular and molecular events leading to renal tubulointerstitial fibrosis. Med Electron Microsc 35:68–80PubMedCrossRefGoogle Scholar
  59. 59.
    Taguchi T, Razzaque MS (2007) The collagen-specific molecular chaperone HSP47: is there a role in fibrosis? Trends Mol Med 13:45–53PubMedCrossRefGoogle Scholar
  60. 60.
    Orrego JJ, Sheehan M (2010) Hyperphosphatemia. Endocr Pract 16:524–525PubMedGoogle Scholar
  61. 61.
    Blokker M (2008) Hyperphosphatemia and its treatment. 1983. CANNT J 18:26–27PubMedGoogle Scholar
  62. 62.
    Baker WL (1985) Hypophosphatemia. Am J Nurs 85:998–1003PubMedGoogle Scholar
  63. 63.
    Malluche HH, Monier-Faugere MC (2000) Hyperphosphatemia: pharmacologic intervention yesterday, today and tomorrow. Clin Nephrol 54:309–317PubMedGoogle Scholar
  64. 64.
    Knochel JP (1981) Hypophosphatemia. West J Med 134:15–26PubMedGoogle Scholar
  65. 65.
    Huybers S, Bindels RJ (2007) Vascular calcification in chronic kidney disease: new developments in drug therapy. Kidney Int 72:663–665PubMedCrossRefGoogle Scholar
  66. 66.
    Razzaque MS (2011) The dualistic role of vitamin D in vascular calcifications. Kidney Int 79:708–714PubMedCrossRefGoogle Scholar
  67. 67.
    Goldsmith DJ, Covic A, Sambrook PA, Ackrill P (1997) Vascular calcification in long-term haemodialysis patients in a single unit: a retrospective analysis. Nephron 77:37–43PubMedCrossRefGoogle Scholar
  68. 68.
    Razzaque MS, St.-Arnaud R, Taguchi T, Lanske B (2005) FGF-23, vitamin D and calcification: the unholy triad. Nephrol Dial Transplant 20:2032–2035PubMedCrossRefGoogle Scholar
  69. 69.
    Goldsmith RS, Ingbar SH (1966) Inorganic phosphate treatment of hypercalcemia of diverse etiologies. N Engl J Med 274:1–7PubMedCrossRefGoogle Scholar
  70. 70.
    Everman DB, Nitu ME, Jacobs BR (2003) Respiratory failure requiring extracorporeal membrane oxygenation after sodium phosphate enema intoxication. Eur J Pediatr 162:517–519PubMedCrossRefGoogle Scholar
  71. 71.
    Marraffa JM, Hui A, Stork CM (2004) Severe hyperphosphatemia and hypocalcemia following the rectal administration of a phosphate-containing Fleet pediatric enema. Pediatr Emerg Care 20:453–456PubMedCrossRefGoogle Scholar
  72. 72.
    Grosskopf I, Graff E, Charach G, Binyamin G, Spinrad S, Blum I (1991) Hyperphosphataemia and hypocalcaemia induced by hypertonic phosphate enema–an experimental study and review of the literature. Hum Exp Toxicol 10:351–355PubMedCrossRefGoogle Scholar
  73. 73.
    Belsey J, Epstein O, Heresbach D (2009) Systematic review: adverse event reports for oral sodium phosphate and polyethylene glycol. Aliment Pharmacol Ther 29:15–28PubMedCrossRefGoogle Scholar
  74. 74.
    Ehrenpreis ED, Parakkal D, Semer R, Du H (2011) Renal risks of sodium phosphate tablets for colonoscopy preparation: a review of adverse drug reactions reported to the US Food and Drug Administration. Colorectal Dis 13:e270–e275PubMedCrossRefGoogle Scholar
  75. 75.
    Jin H, Xu C-X, Lim H-T, Park S-J, Shin J-Y, Chung Y-S et al (2009) High dietary inorganic phosphate increases lung tumorigenesis and alters Akt signaling. Am J Respir Crit Care Med 179:59–68PubMedCrossRefGoogle Scholar
  76. 76.
    Nabeshima Y (2002) Klotho: a fundamental regulator of aging. Ageing Res Rev 1:627–638PubMedCrossRefGoogle Scholar
  77. 77.
    Kuro-o M (2001) Disease model: human aging. Trends Mol Med 7:179–181PubMedCrossRefGoogle Scholar
  78. 78.
    Nabeshima Y (2006) Toward a better understanding of Klotho. Sci Aging Knowledge Environ 2006:pe11Google Scholar
  79. 79.
    Martin RR, Lisehora GR, Braxton M Jr, Barcia PJ (1987) Fatal poisoning from sodium phosphate enema. Case report and experimental study. JAMA 257:2190–2192PubMedCrossRefGoogle Scholar
  80. 80.
    Ohnishi M, Kato S, Razzaque MS (2011) Genetic induction of phosphate toxicity significantly reduces the survival of hypercholesterolemic obese mice. Biochem Biophys Res Commun 415:434–438 (doi:10.1016/j.bbrc.2011.10.076)
  81. 81.
    Pietsch JB, Shizgal HM, Meakins JL (1977) Injury by hypertonic phosphate enema. Can Med Assoc J 116:1169–1170PubMedGoogle Scholar
  82. 82.
    Yamazaki M, Ozono K, Okada T, Tachikawa K, Kondou H, Ohata Y et al (2010) Both FGF23 and extracellular phosphate activate Raf/MEK/ERK pathway via FGF receptors in HEK293 cells. J Cell Biochem 111:1210–1221PubMedCrossRefGoogle Scholar
  83. 83.
    Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G (2005) Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation 112:2627–2633PubMedCrossRefGoogle Scholar
  84. 84.
    Dhingra R, Sullivan LM, Fox CS, Wang TJ, D’Agostino RB Sr, Gaziano JM et al (2007) Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med 167:879–885PubMedCrossRefGoogle Scholar
  85. 85.
    Foley RN, Collins AJ, Herzog CA, Ishani A, Kalra PA (2009) Serum phosphorus levels associate with coronary atherosclerosis in young adults. J Am Soc Nephrol 20:397–404PubMedCrossRefGoogle Scholar
  86. 86.
    Foley RN, Collins AJ, Ishani A, Kalra PA (2008) Calcium-phosphate levels and cardiovascular disease in community-dwelling adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J 156:556–563PubMedCrossRefGoogle Scholar
  87. 87.
    Kestenbaum B, Glazer NL, Kottgen A, Felix JF, Hwang SJ, Liu Y et al (2010) Common genetic variants associate with serum phosphorus concentration. J Am Soc Nephrol 21:1223–1232PubMedCrossRefGoogle Scholar
  88. 88.
    Tani Y, Sato T, Yamanaka-Okumura H, Yamamoto H, Arai H, Sawada N et al (2007) Effects of prolonged high phosphorus diet on phosphorus and calcium balance in rats. J Clin Biochem Nutr 40:221–228PubMedCrossRefGoogle Scholar
  89. 89.
    Huttunen MM, Tillman I, Viljakainen HT, Tuukkanen J, Peng Z, Pekkinen M et al (2007) High dietary phosphate intake reduces bone strength in the growing rat skeleton. J Bone Miner Res 22:83–92PubMedCrossRefGoogle Scholar
  90. 90.
    Calvo MS (1993) Dietary phosphorus, calcium metabolism and bone. J Nutr 123:1627–1633PubMedGoogle Scholar
  91. 91.
    Kemi VE, Karkkainen MU, Rita HJ, Laaksonen MM, Outila TA, Lamberg-Allardt CJ (2010) Low calcium:phosphorus ratio in habitual diets affects serum parathyroid hormone concentration and calcium metabolism in healthy women with adequate calcium intake. Br J Nutr 103:561–568PubMedCrossRefGoogle Scholar
  92. 92.
    Bai RJ, Cheng XG, Yan D, Qian ZH, Li XM, Qu H et al (2011) Rabbit model of primary hyperparathyroidism induced by high-phosphate diet. Domest Anim Endocrinol. doi:10.1016/j.domaniend.2011.09.001
  93. 93.
    Bacchetta J, Salusky IB (2011) Evaluation of hypophosphatemia: lessons from patients with genetic disorders. Am J Kidney Dis. doi:10.1053/j.ajkd.2011.08.035

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© The Japanese Society for Bone and Mineral Research and Springer 2012

Authors and Affiliations

  1. 1.Department of Oral Medicine, Infection and ImmunityHarvard School of Dental MedicineBostonUSA
  2. 2.Department of PathologyNagasaki University Graduate School of Biomedical SciencesNagasakiJapan

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