Phosphate Control of PTH Secretion

  • Piergiorgio MessaEmail author


Phosphate is not only one of the main components of the mineral phase of the bone, but it also plays many key biological roles. Its serum levels and balance are under the control of a great number of factors. In turn, phosphorus can control all these factors, through a complex network of mechanisms. Among these factors, PTH represents one of the main controllers of phosphorus metabolism, and phosphorus, in turn, has a manifold control of PTH itself, by both indirect and direct pathways. Though the indirect mechanisms through which phosphate controls PTH are at least in part well defined, the putative direct ones are by far less understood. There is sparse evidence that a system directly sensing phosphorus concentration is present in plants and unicellular organisms and probably also in some cellular systems of multicellular organisms (intestinal, renal, and bone cells), though it is not completely clear how they work. The possibility of the presence of such a phosphorus sensing mechanism has been hypothesized also for the parathyroid cells, suggesting many potential pathways, mainly based on experimental studies. However, it is still far from being definitively demonstrated.


Phosphorus PTH Parathyroid glands Phosphate metabolism Phosphorus sensor 


  1. 1.
    Kornberg A (1979) The enzymatic replication of DNA. CRC Crit Rev Biochem 7:23–43CrossRefPubMedGoogle Scholar
  2. 2.
    Krebs EG, Beavo JA (1979) Phosphorylation-dephosphorylation of enzymes. Annu Rev Biochem 48:923–959CrossRefPubMedGoogle Scholar
  3. 3.
    Lardy HA, Ferguson SM (1969) Oxidative phosphorylation in mitochondria. Annu Rev Biochem 38:991–1034CrossRefPubMedGoogle Scholar
  4. 4.
    Bevington A, Brough D, Baker FE, Hattersley J, Walls J (1995) Metabolic acidosis is a potent stimulus for cellular inorganic phosphate generation in uraemia. Clin Sci (Lond) 88(4):405–412Google Scholar
  5. 5.
    Fleisch H (1980) Homeostasis of inorganic phosphate. In: Urist MR (ed) Fundamental and clinical bone physiology. Lippincott, PhiladelphiaGoogle Scholar
  6. 6.
    Lee DB, Walling MW, Brautbar N (1986) Intestinal phosphate absorption: influence of vitamin D and nonvitamin D factors. Am J Physiol Gastrointest Liver Physiol 250:G369–G373Google Scholar
  7. 7.
    Segawa H, Kaneko I, Yamanaka S, Ito M, Kuwahata M, Inoue Y, Kato S, Miyamoto K (2004) Intestinal Na-P(i) cotransporter adaptation to dietary P(i) content in vitamin D receptor null mice. Am J Physiol Renal Physiol 287:F39–F47CrossRefPubMedGoogle Scholar
  8. 8.
    Berndt T, Kumar R (2009) Novel mechanisms in the regulation of phosphorus homeostasis. Physiology (Bethesda) 24:17–25CrossRefGoogle Scholar
  9. 9.
    Hruska K, Slatopolsky E (1996) Disorders of phosphorous, calcium, and magnesium metabolism. In: Schrier R, Gottschalk C (eds) Diseases of the kidney. Little, Brown, and Company, London, pp 2477–2526Google Scholar
  10. 10.
    Kronenberg HM (2002) NPT2a—the key to phosphate homeostasis. N Engl J Med 347:1022–1024CrossRefPubMedGoogle Scholar
  11. 11.
    Tanimura A, Yamada F, Saito A, Ito M, Kimura T, Anzai N, Horie D, Yamamoto H, Miyamoto K, Taketani Y, Takeda E (2011) Analysis of different complexes of type IIa sodium-dependent phosphate transporter in rat renal cortex using blue-native polyacrylamide gel ecletrophoresis. J Med Invest 58(1–2):140–147CrossRefPubMedGoogle Scholar
  12. 12.
    Forster IC, Hernando N, Biber J, Murer H (2013) Phosphate transporters of the SLC20 and SLC34 families. Mol Aspects Med 34(2–3):386–395CrossRefPubMedGoogle Scholar
  13. 13.
    Gattineni J, Alphonse P, Zhang Q, Mathews N, Bates CM, Baum M (2014) Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4. Am J Physiol Renal Physiol 306(3):F351–F358CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Dallas SL, Prideaux M, Bonewald LF (2013) The osteocyte: an endocrine cell … and more. Endocr Rev 34(5):658–690CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Wesseling-Perry K, Jüppner H (2013) The osteocyte in CKD: new concepts regarding the role of FGF23 in mineral metabolism and systemic complications. Bone 54:222–229CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    DeLuca HF (2004) Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr 80:1689S–1696SPubMedGoogle Scholar
  17. 17.
    Aurbach GD, Heath DA (1974) Parathyroid hormone and calcitonin regulation of renal function. Kidney Int 6(5):331–345CrossRefPubMedGoogle Scholar
  18. 18.
    Berndt TJ, Schiavi S, Kumar R (2005) “Phosphatonins” and the regulation of phosphorus homeostasis. Am J Physiol Renal Physiol 289(6):F1170–F1182CrossRefPubMedGoogle Scholar
  19. 19.
    Feng JQ, Clinkenbeard EL, Yuan B, White KE, Drezner MK (2013) Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia. Bone 54(2):213–221CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Berndt T, Thomas LF, Craig TA, Sommer S, Li X, Bergstralh EJ, Kumar R (2007) Evidence for a signaling axis by which intestinal phosphate rapidly modulates renal phosphate reabsorption. Proc Natl Acad Sci U S A 104(26):11085–11090CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Burnett SM, Gunawardene SC, Bringhurst FR et al (2006) Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J Bone Miner Res 21(8):1187–1196CrossRefPubMedGoogle Scholar
  22. 22.
    Ferrari SL, Bonjour JP, Rizzoli R (2005) Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J Clin Endocrinol Metab 90:1519–1524CrossRefPubMedGoogle Scholar
  23. 23.
    Baxter LA, DeLuca HF (1976) Stimulation of 25-hydroxy-vitamin D3-1α- hydroxylase by phosphate depletion. J Biol Chem 251:3158–3161PubMedGoogle Scholar
  24. 24.
    Bellido T, Saini V, Pajevic PD (2013) Effects of PTH on osteocyte function. Bone 54(2):250–257CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Kaplan MA, Canterbury JM, Gavellas G, Jaffe D, Bourgoignie JJ, Reiss E, Bricker NS (1978) Interrelations between phosphorus, calcium, parathyroid hormone, and renal phosphate excretion in response to an oral phosphorus load in normal and uremic dogs. Kidney Int 14:207–214CrossRefPubMedGoogle Scholar
  26. 26.
    Boyle IT, Gray RW, DeLuca HF (1971) Regulation by calcium of in vivo synthesis of 1,25-dihydroxycholecalciferol and 21,25-dihydroxycholecalciferol. Proc Natl Acad Sci U S A 68:2131–2134CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Tanaka Y, DeLuca HF (1973) The control of 25-hydroxyvitamin D metabolism by inorganic phosphorus. Arch Biochem Biophys 154:566–574CrossRefPubMedGoogle Scholar
  28. 28.
    Razzaque MS (2009) The FGF23–Klotho axis: endocrine regulation of phosphate homeostasis. Nat Rev Endocrinol 5:611–619CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Saini RK, Kaneko I, Jurutka PW, Forster R, Hsieh A, Hsieh JC, Haussler MR, Whitfield GK (2013) 1,25-dihydroxyvitamin D(3) regulation of fibroblast growth factor-23 expression in bone cells: evidence for primary and secondary mechanisms modulated by leptin and interleukin-6. Calcif Tissue Int 92(4):339–353CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J (2007) The parathyroid is a target organ for FGF23 in rats. J Clin Invest 117(12):4003–4008PubMedCentralPubMedGoogle Scholar
  31. 31.
    Krajisnik T, Bjorklund P, Marsell R et al (2007) Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 195:125–131CrossRefPubMedGoogle Scholar
  32. 32.
    Komaba H, Fukagawa M (2010) FGF23–parathyroid interaction: implications in chronic kidney disease. Kidney Int 77:292–298CrossRefPubMedGoogle Scholar
  33. 33.
    Silver J, Naveh-Many T, Mayer H et al (1986) Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest 78:1296–1301CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Silver J, Russell J, Sherwood LM (1985) Regulation by vitamin D metabolites of messenger ribonucleic acid for preproparathyroid hormone in isolated bovine parathyroid cells. Proc Natl Acad Sci U S A 82:4270–4273CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    Cantley LK, Russell J, Lettieri D, Sherwood LM (1985) 1,25-Dihydroxyvitamin D3 suppresses parathyroid hormone secretion from bovine parathyroid cells in tissue culture. Endocrinology 117:2114–2119CrossRefPubMedGoogle Scholar
  36. 36.
    Russell J, Lettieri D, Sherwood LM (1986) Suppression by 1,25(OH)2D3 of transcription of the pre-proparathyroid hormone gene. Endocrinology 119:2864–2866CrossRefPubMedGoogle Scholar
  37. 37.
    Brown AJ, Dusso A, Lopez-Hilker S, Lewis-Finch J, Grooms P, Slatopolsky E (1989) 1,25-(OH)2D receptors are decreased in parathyroid glands from chronically uremic dogs. Kidney Int 35:19–23CrossRefPubMedGoogle Scholar
  38. 38.
    Perwad F, Azam N, Zhang MY, Yamashita T, Tenenhouse HS, Portale AA (2005) Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology 146(12):5358–5364CrossRefPubMedGoogle Scholar
  39. 39.
    Sommer S, Berndt T, Craig T, Kumar R (2007) The phosphatonins and the regulation of phosphate transport and vitamin D metabolism. J Steroid Biochem Mol Biol 103:497–503CrossRefPubMedGoogle Scholar
  40. 40.
    Ito N, Fukumoto S, Takeuchi Y, Takeda S, Suzuki H, Yamashita T, Fujita T (2007) Effect of acute changes of serum phosphate on fibroblast growth factor (FGF)23 levels in humans. J Bone Miner Metab 25:419–422CrossRefPubMedGoogle Scholar
  41. 41.
    Larsson T, Nisbeth U, Ljunggren O, Juppner H, Jonsson KB (2003) Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int 64:2272–2279CrossRefPubMedGoogle Scholar
  42. 42.
    Martin DR, Ritter CS, Slatopolsky E et al (2005) Acute regulation of parathyroid hormone by dietary phosphate. Am J Physiol Endocrinol Metab 289:E729–E734CrossRefPubMedGoogle Scholar
  43. 43.
    Kuo HF, Chiou TJ (2011) The role of microRNAs in phosphorus deficiency signaling. Plant Physiol 156(3):1016–1024CrossRefPubMedCentralPubMedGoogle Scholar
  44. 44.
    Suzuki S, Ferjani A, Suzuki I, Murata N (2004) The SphS-SphR two component system is the exclusive sensor for the induction of gene expression in response to phosphate limitation in synechocystis. J Biol Chem 279(13):13234–13240CrossRefPubMedGoogle Scholar
  45. 45.
    Mouillon JM, Persson BL (2006) New aspects on phosphate sensing and signaling in Saccharomyces cerevisiae. FEMS Yeast Res 6:171–176CrossRefPubMedGoogle Scholar
  46. 46.
    Lamarche MG, Wanner BL, Crepin S, Harel J (2008) The phosphate regulon and bacterial virulence: a regulatory network connecting phosphate homeostasis and pathogenesis. FEMS Microbiol Rev 32:461–473CrossRefPubMedGoogle Scholar
  47. 47.
    Markovich D, Verri T, Sorribas V, Forgo J, Biber J, Murer H (1995) Regulation of opossum kidney (OK) cell Na/Pi cotransport by Pi deprivation involves mRNA stability. Pflugers Arch 430:459–463CrossRefPubMedGoogle Scholar
  48. 48.
    Fujita T, Izumo N, Fukuyama R, Meguro T, Nakamuta H, Kohno T, Koida M (2001) Phosphate provides an extracellular signal that drives nuclear export of Runx2/Cbfa1 in bone cells. Biochem Biophys Res Commun 280:348–352CrossRefPubMedGoogle Scholar
  49. 49.
    Slatopolsky E, Caglar S, Gradowska L et al (1972) On the prevention of secondary hyperparathyroidism in experimental chronic renal disease using ‘proportional reduction’ of dietary phosphorus intake. Kidney Int 2:147–151CrossRefPubMedGoogle Scholar
  50. 50.
    Lopez-Hilker S, Dusso AS, Rapp NS et al (1990) Phosphorus restriction reverses hyperparathyroidism in uremia independent of changes in calcium and calcitriol. Am J Physiol 259:F432–F437PubMedGoogle Scholar
  51. 51.
    Almaden Y, Canalejo A, Hernandez A et al (1996) Direct effect of phosphorus on PTH secretion from whole rat parathyroid glands in vitro. J Bone Miner Res 11:970–976CrossRefPubMedGoogle Scholar
  52. 52.
    Nielsen PK, Feldt-Rasmussen U, Olgaard K (1996) A direct effect in vitro of phosphate on PTH release from bovine parathyroid tissue slices but not from dispersed parathyroid cells. Nephrol Dial Transplant 11:1762–1768CrossRefPubMedGoogle Scholar
  53. 53.
    Kilav R, Silver J, Naveh-Many T (1995) Parathyroid hormone gene expression in hypophosphatemic rats. J Clin Invest 96:327–333CrossRefPubMedCentralPubMedGoogle Scholar
  54. 54.
    Silver J, Naveh-Many T (2009) Phosphate and the parathyroid. Kidney Int 75:898–905CrossRefPubMedGoogle Scholar
  55. 55.
    Ritter CS, Martin DR, Lu Y et al (2002) Reversal of secondary hyperparathyroidism by phosphate restriction restores parathyroid calcium-sensing receptor expression and function. J Bone Miner Res 17:2206–2213CrossRefPubMedGoogle Scholar
  56. 56.
    Dusso AS, Pavlopoulos T, Naumovich L et al (2001) p21WAF1 and transforming growth factor-a mediate dietary phosphate regulation of parathyroid cell growth. Kidney Int 59:855–865CrossRefPubMedGoogle Scholar
  57. 57.
    Cozzolino M, Lu Y, Sato T et al (2005) A critical role for enhanced TGF-a and EGFR expression in the initiation of parathyroid hyperplasia in experimental kidney disease. Am J Physiol Renal Physiol 289:F1096–F1102CrossRefPubMedGoogle Scholar
  58. 58.
    Dusso A, Arcidiacono MV, Yang J et al (2010) Vitamin D inhibition of TACE and prevention of renal osteodystrophy and cardiovascular mortality. J Steroid Biochem Mol Biol 121:193–198CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia 2015

Authors and Affiliations

  1. 1.Department of Nephrology, Urology and Renal TransplantFondazione Ca’ Granda IRCCS Ospedale Maggiore PoliclinicoMilanItaly

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