Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Hormonal regulation of biomineralization

Abstract

Biomineralization is the process by which organisms produce mineralized tissues. This crucial process makes possible the rigidity and flexibility that the skeleton needs for ambulation and protection of vital organs, and the hardness that teeth require to tear and grind food. The skeleton also serves as a source of mineral in times of short supply, and the intestines absorb and the kidneys reclaim or excrete minerals as needed. This Review focuses on physiological and pathological aspects of the hormonal regulation of biomineralization. We discuss the roles of calcium and inorganic phosphate, dietary intake of minerals and the delicate balance between activators and inhibitors of mineralization. We also highlight the importance of tight regulation of serum concentrations of calcium and phosphate, and the major regulators of biomineralization: parathyroid hormone (PTH), the vitamin D system, vitamin K, fibroblast growth factor 23 (FGF23) and phosphatase enzymes. Finally, we summarize how developmental stresses in the fetus and neonate, and in the mother during pregnancy and lactation, invoke alternative hormonal regulatory pathways to control mineral delivery, skeletal metabolism and biomineralization.

Key points

  • Biomineralization is the process by which organisms produce mineralized tissues, such as tooth enamel and bone.

  • In land-based vertebrates, the skeleton also serves as a source of mineral in times of short supply, and the intestines absorb and the kidneys reclaim or excrete minerals as needed.

  • Tight regulation of serum concentrations of calcium and inorganic phosphate are required for appropriate biomineralization.

  • The major regulators of biomineralization are parathyroid hormone, the vitamin D system, vitamin K, fibroblast growth factor 23 and phosphatase enzymes.

  • Pregnancy and development cause unique stresses to the fetus, neonate and mother; these conditions invoke alternative hormonal regulatory pathways to control mineral delivery, skeletal metabolism and biomineralization.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Regulation of calcium and phosphate economy and bone mass.
Fig. 2: Activators and inhibitors of mineralization.
Fig. 3: Calcitriol–VDR-stimulated calcium transport in intestinal epithelium.
Fig. 4: Role of matrix Gla protein in mineralization.
Fig. 5: Relationship of serum concentrations of calcium and PTH.
Fig. 6: Regulation of mineral homeostasis before and after birth.

References

  1. 1.

    Vannucci, L. et al. Calcium intake in bone health: a focus on calcium-rich mineral waters. Nutrients 10, 1930 (2018).

    PubMed Central  Google Scholar 

  2. 2.

    Boivin, G. & Meunier, P. J. The degree of mineralization of bone tissue measured by computerized quantitative contact microradiography. Calcif. Tissue Int. 70, 503–511 (2002).

    CAS  PubMed  Google Scholar 

  3. 3.

    Millan, J. L. The role of phosphatases in the initiation of skeletal mineralization. Calcif. Tissue Int. 93, 299–306 (2013).

    CAS  PubMed  Google Scholar 

  4. 4.

    Michigami, T. & Ozono, K. Roles of phosphate in skeleton. Front. Endocrinol. 10, 180 (2019).

    Google Scholar 

  5. 5.

    Solomon, D. H., Browning, J. A. & Wilkins, R. J. Inorganic phosphate transport in matrix vesicles from bovine articular cartilage. Acta Physiol. 190, 119–125 (2007).

    CAS  Google Scholar 

  6. 6.

    Yadav, M. C. et al. Skeletal mineralization deficits and impaired biogenesis and function of chondrocyte-derived matrix vesicles in phospho1(-/-) and phospho1/Pit1 double-knockout mice. J. Bone Min. Res. 31, 1275–1286 (2016).

    CAS  Google Scholar 

  7. 7.

    Yadav, M. C. et al. Loss of skeletal mineralization by the simultaneous ablation of PHOSPHO1 and alkaline phosphatase function: a unified model of the mechanisms of initiation of skeletal calcification. J. Bone Min. Res. 26, 286–297 (2011).

    CAS  Google Scholar 

  8. 8.

    Roschger, A. et al. Newly formed and remodeled human bone exhibits differences in the mineralization process. Acta Biomater. 104, 221–230 (2020).

    CAS  PubMed  Google Scholar 

  9. 9.

    Moreira, C. A., Dempster, D. W. & Baron, R. Anatomy and ultrastructure of bone - histogenesis, growth and remodeling. Endotext [Internet] https://pubmed.ncbi.nlm.nih.gov/25905372/ (updated 5 Jun 2019).

  10. 10.

    Winzenberg, T., Shaw, K., Fryer, J. & Jones, G. Effects of calcium supplementation on bone density in healthy children: meta-analysis of randomised controlled trials. Br. Med. J. 333, 775 (2006).

    CAS  Google Scholar 

  11. 11.

    Harvey, N. C. et al. The role of calcium supplementation in healthy musculoskeletal ageing: An expert consensus meeting of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the International Foundation for Osteoporosis (IOF). Osteoporos. Int. 28, 447–462 (2017).

    CAS  PubMed  Google Scholar 

  12. 12.

    Tai, V., Leung, W., Grey, A., Reid, I. R. & Bolland, M. J. Calcium intake and bone mineral density: systematic review and meta-analysis. Br. Med. J. 351, h4183 (2015).

    Google Scholar 

  13. 13.

    Ziegler, E. E., O’Donnell, A. M., Nelson, S. E. & Fomon, S. J. Body composition of the reference fetus. Growth 40, 329–341 (1976).

    CAS  PubMed  Google Scholar 

  14. 14.

    Widdowson, E. M. & Dickerson, J. W. in Mineral Metabolism: An Advanced Treatise, Volume II, The Elements, Part A (eds Comar, C. L. & Bronner, F.) 1–247 (Academic Press, 1964).

  15. 15.

    Widdowson, E. M. & McCance, R. A. The metabolism of calcium, phosphorus, magnesium and strontium. Pediatr. Clin. North Am. 12, 595–614 (1965).

    CAS  PubMed  Google Scholar 

  16. 16.

    Sparks, J. W. Human intrauterine growth and nutrient accretion. Semin. Perinatol. 8, 74–93 (1984).

    CAS  PubMed  Google Scholar 

  17. 17.

    Givens, M. H. & Macy, I. C. The chemical composition of the human fetus. J. Biol. Chem. 102, 7–17 (1933).

    CAS  Google Scholar 

  18. 18.

    Trotter, M. & Hixon, B. B. Sequential changes in weight, density, and percentage ash weight of human skeletons from an early fetal period through old age. Anat. Rec. 179, 1–18 (1974).

    CAS  PubMed  Google Scholar 

  19. 19.

    Comar, C. L. Radiocalcium studies in pregnancy. Ann. NY Acad. Sci. 64, 281–298 (1956).

    CAS  Google Scholar 

  20. 20.

    Fomon, S. J. & Nelson, S. E. In Nutrition of Normal Infants (ed. Fomon, S. J.) 192–211 (Mosby, 1993).

  21. 21.

    Widdowson, E. M. Metabolic relationship of calcium, magnesium and phosphorus in the foetus and newly born. Voeding 23, 62–71 (1962).

    CAS  PubMed  Google Scholar 

  22. 22.

    Best, C. H. & Taylor, N. B. In The Physiological Basis of Medical Practice, 3rd Edition (eds Best, C. H. & Taylor, N. B.) 1124–1159 (Williams and Wilkins, 1940).

  23. 23.

    Widdowson, E. M. in Scientific Foundations of Paediatrics (eds Davis, J. A. & Dobbing, J.) 330–342 (William Heinemann, 1981).

  24. 24.

    Bozzetti, V. & Tagliabue, P. Metabolic bone disease in preterm newborn: an update on nutritional issues. Ital. J. Pediatr. 35, 20 (2009).

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Kovacs, C. S. & Kronenberg, H. M. Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation. Endocr. Rev. 18, 832–872 (1997).

    CAS  PubMed  Google Scholar 

  26. 26.

    Care, A. D. The placental transfer of calcium. J. Dev. Physiol. 15, 253–257 (1991).

    CAS  PubMed  Google Scholar 

  27. 27.

    Weisman, Y. et al. 1α, 25-Dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 in vitro synthesis by human decidua and placenta. Nature 281, 317–319 (1979).

    CAS  PubMed  Google Scholar 

  28. 28.

    Rigo, J. & Senterre, J. Nutritional needs of premature infants: current issues. J. Pediatrics 149, S80–S88 (2006).

    CAS  Google Scholar 

  29. 29.

    Ryan, S., Congdon, P. J., James, J., Truscott, J. & Horsman, A. Mineral accretion in the human fetus. Arch. Dis. Child. 63, 799–808 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Glimcher, M. J., Hodge, A. J. & Schmitt, F. O. Macromolecular aggregation states in relation to mineralization: the collagen-hydroxyapatite system as studied in vitro. Proc. Natl Acad. Sci. USA 43, 860–867 (1957).

    CAS  PubMed  Google Scholar 

  31. 31.

    Fleisch, H. & Bisaz, S. Mechanism of calcification: inhibitory role of pyrophosphate. Nature 195, 911 (1962).

    CAS  PubMed  Google Scholar 

  32. 32.

    Block, G. A., Hulbert-Shearon, T. E., Levin, N. W. & Port, F. K. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am. J. Kidney Dis. 31, 607–617 (1998).

    CAS  PubMed  Google Scholar 

  33. 33.

    Gutierrez, O. M. et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N. Engl. J. Med. 359, 584–592 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Dhingra, R. et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch. Intern. Med. 167, 879–885 (2007).

    CAS  PubMed  Google Scholar 

  35. 35.

    Chang, A. R. & Grams, M. E. Serum phosphorus and mortality in the Third National Health and Nutrition Examination Survey (NHANES III): effect modification by fasting. Am. J. Kidney Dis. 64, 567–573 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Levi, M. et al. Mechanisms of phosphate transport. Nat. Rev. Nephrol. 15, 482–500 (2019).

    CAS  PubMed  Google Scholar 

  37. 37.

    Christov, M. & Juppner, H. Phosphate homeostasis disorders. Best. Pract. Res. Clin. Endocrinol. Metab. 32, 685–706 (2018).

    CAS  PubMed  Google Scholar 

  38. 38.

    Karim, Z. et al. NHERF1 mutations and responsiveness of renal parathyroid hormone. N. Engl. J. Med. 359, 1128–1135 (2008).

    CAS  PubMed  Google Scholar 

  39. 39.

    Gattineni, J. & Friedman, P. A. Regulation of hormone-sensitive renal phosphate transport. Vitam. Horm. 98, 249–306 (2015).

    CAS  PubMed  Google Scholar 

  40. 40.

    Wheeler, J. A. & Clinkenbeard, E. L. Regulation of fibroblast growth factor 23 by iron, EPO, and HIF. Curr. Mol. Biol. Rep. 5, 8–17 (2019).

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    David, V. et al. Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int. 89, 135–146 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Hanudel, M. R. et al. Effects of erythropoietin on fibroblast growth factor 23 in mice and humans. Nephrol. Dia. Transplant. 34, 2057–2065 (2019).

    CAS  Google Scholar 

  43. 43.

    Villa-Bellosta, R. et al. The Na+-Pi cotransporter PiT-2 (SLC20A2) is expressed in the apical membrane of rat renal proximal tubules and regulated by dietary Pi. Am. J. Physiol. Ren. Physiol. 296, F691–F699 (2009).

    CAS  Google Scholar 

  44. 44.

    Beck-Cormier, S. et al. Slc20a2, encoding the phosphate transporter PiT2, is an important genetic determinant of bone quality and strength. J. Bone Min. Res. 34, 1101–1114 (2019).

    CAS  Google Scholar 

  45. 45.

    Giovannini, D., Touhami, J., Charnet, P., Sitbon, M. & Battini, J. L. Inorganic phosphate export by the retrovirus receptor XPR1 in metazoans. Cell Rep. 3, 1866–1873 (2013).

    CAS  PubMed  Google Scholar 

  46. 46.

    Ansermet, C. et al. Renal Fanconi syndrome and hypophosphatemic rickets in the absence of xenotropic and polytropic retroviral receptor in the nephron. J. Am. Soc. Nephrol. 28, 1073–1078 (2017).

    CAS  PubMed  Google Scholar 

  47. 47.

    Yao, X. P. et al. Analysis of gene expression and functional characterization of XPR1: a pathogenic gene for primary familial brain calcification. Cell Tissue Res. 370, 267–273 (2017).

    CAS  PubMed  Google Scholar 

  48. 48.

    Legati, A. et al. Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export. Nat. Genet. 47, 579–581 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Xu, X. et al. Murine placental-fetal phosphate dyshomeostasis caused by an Xpr1 deficiency accelerates placental calcification and restricts fetal growth in late gestation. J. Bone Min. Res. 35, 116–129 (2020).

    CAS  Google Scholar 

  50. 50.

    Li, X. et al. Control of XPR1-dependent cellular phosphate efflux by InsP8 is an exemplar for functionally-exclusive inositol pyrophosphate signaling. Proc. Natl Acad. Sci. USA 117, 3568–3574 (2020).

    CAS  PubMed  Google Scholar 

  51. 51.

    Wilson, M. S., Jessen, H. J. & Saiardi, A. The inositol hexakisphosphate kinases IP6K1 and -2 regulate human cellular phosphate homeostasis, including XPR1-mediated phosphate export. J. Biol. Chem. 294, 11597–11608 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Burnett, S. M. et al. Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J. Bone Min. Res. 21, 1187–1196 (2006).

    CAS  Google Scholar 

  53. 53.

    Chande, S. & Bergwitz, C. Role of phosphate sensing in bone and mineral metabolism. Nat. Rev. Endocrinol. 14, 637–655 (2018).

    CAS  PubMed  Google Scholar 

  54. 54.

    Fukumoto, S., Takashi, Y., Tsoumpra, M. K., Sawatsubashi, S. & Matsumoto, T. How do we sense phosphate to regulate serum phosphate level? J. Bone Min. Metab. 38, 1–6 (2020).

    CAS  Google Scholar 

  55. 55.

    Simic, P. et al. Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney. J. Clin. Invest. 130, 1513–1526 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Centeno, P. P. et al. Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion. Nat. Commun. 10, 4693 (2019).

    PubMed  PubMed Central  Google Scholar 

  57. 57.

    Prie, D. et al. Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N. Engl. J. Med. 347, 983–991 (2002).

    CAS  PubMed  Google Scholar 

  58. 58.

    Bergwitz, C. et al. SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis. Am. J. Hum. Genet. 78, 179–192 (2006).

    CAS  PubMed  Google Scholar 

  59. 59.

    Mannstadt, M. et al. Hypoparathyroidism. Nat. Rev. Dis. Prim. 3, 17080 (2017).

    PubMed  Google Scholar 

  60. 60.

    Minisola, S. et al. Tumour-induced osteomalacia. Nat. Rev. Dis. Prim. 3, 17044 (2017).

    PubMed  Google Scholar 

  61. 61.

    Orriss, I. R., Arnett, T. R. & Russell, R. G. Pyrophosphate: a key inhibitor of mineralisation. Curr. Opin. Pharmacol. 28, 57–68 (2016).

    CAS  PubMed  Google Scholar 

  62. 62.

    Rutsch, F. et al. Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat. Genet. 34, 379–381 (2003).

    CAS  PubMed  Google Scholar 

  63. 63.

    Lomashvili, K. A., Narisawa, S., Millan, J. L. & O’Neill, W. C. Vascular calcification is dependent on plasma levels of pyrophosphate. Kidney Int. 85, 1351–1356 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Whyte, M. P. Hypophosphatasia — aetiology, nosology, pathogenesis, diagnosis and treatment. Nat. Rev. Endocrinol. 12, 233–246 (2016).

    CAS  PubMed  Google Scholar 

  65. 65.

    Thomas, L. et al. Pharmacological Npt2a inhibition causes phosphaturia and reduces plasma phosphate in mice with normal and reduced kidney function. J. Am. Soc. Nephrol. 30, 2128–2139 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Christakos, S., Dhawan, P., Verstuyf, A., Verlinden, L. & Carmeliet, G. Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol. Rev. 96, 365–408 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Goltzman, D. Functions of vitamin D in bone. Histochem. Cell Biol. 149, 305–312 (2018).

    CAS  PubMed  Google Scholar 

  68. 68.

    Munns, C. F. et al. Global consensus recommendations on prevention and management of nutritional rickets. J. Clin. Endocrinol. Metab. 101, 394–415 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Christakos, S. et al. Vitamin D and the intestine: review and update. J. Steroid Biochem. Mol. Biol. 196, 105501 (2020).

    CAS  PubMed  Google Scholar 

  70. 70.

    Ammann, P., Rizzoli, R. & Fleisch, H. Calcium absorption in rat large intestine in vivo: availability of dietary calcium. Am. J. Physiol. 251, G14–G18 (1986).

    CAS  PubMed  Google Scholar 

  71. 71.

    Rizzoli, R. Nutritional influence on bone: role of gut microbiota. Aging Clin. Exp. Res. 31, 743–751 (2019).

    PubMed  Google Scholar 

  72. 72.

    Rizzoli, R., Fleisch, H. & Bonjour, J. P. Role of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) on intestinal inorganic phosphate (Pi) absorption in rats with normal vitamin D supply. Calcif. Tissue Res. 22 (Suppl.), 561–562 (1977).

    PubMed  Google Scholar 

  73. 73.

    Dhawan, P. et al. Transgenic expression of the vitamin D receptor restricted to the ileum, cecum, and colon of vitamin D receptor knockout mice rescues vitamin D receptor-dependent rickets. Endocrinology 158, 3792–3804 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    McCollum, E. V., Simmonds, N., Shipley, P. G. & Park, E. A. Studies on experimental rickets. XV. The effect of starvation on the healing of rickets. Bull. Johns Hopkins Hosp. 33, 31–33 (1922).

    CAS  Google Scholar 

  75. 75.

    Sabbagh, Y., Carpenter, T. O. & Demay, M. B. Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. Proc. Natl Acad. Sci. USA 102, 9637–9642 (2005).

    CAS  PubMed  Google Scholar 

  76. 76.

    Underwood, J. L. & DeLuca, H. F. Vitamin D is not directly necessary for bone growth and mineralization. Am. J. Physiol. 246, E493–498 (1984).

    CAS  PubMed  Google Scholar 

  77. 77.

    Amling, M. et al. Rescue of the skeletal phenotype of vitamin D receptor-ablated mice in the setting of normal mineral ion homeostasis: formal histomorphometric and biomechanical analyses. Endocrinology 140, 4982–4987 (1999).

    CAS  PubMed  Google Scholar 

  78. 78.

    Dardenne, O., Prud’homme, J., Hacking, S. A., Glorieux, F. H. & St-Arnaud, R. Correction of the abnormal mineral ion homeostasis with a high-calcium, high-phosphorus, high-lactose diet rescues the PDDR phenotype of mice deficient for the 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1). Bone 32, 332–340 (2003).

    CAS  PubMed  Google Scholar 

  79. 79.

    Panda, D. K. et al. Inactivation of the 25-hydroxyvitamin D 1α-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis. J. Biol. Chem. 279, 16754–16766 (2004).

    CAS  PubMed  Google Scholar 

  80. 80.

    Rizzoli, R., Fleisch, H. & Bonjour, J. P. Effect of thyroparathyroidectomy of calcium metabolism in rats: role of 1,25-dihydroxyvitamin D3. Am. J. Physiol. 233, E160–E164 (1977).

    CAS  PubMed  Google Scholar 

  81. 81.

    Pike, J. W. & Christakos, S. Biology and mechanisms of action of the vitamin D hormone. Endocrinol. Metab. Clin. North. Am. 46, 815–843 (2017).

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Haussler, M. R. et al. Molecular mechanisms of vitamin D action. Calcif. Tissue Int. 92, 77–98 (2013).

    CAS  Google Scholar 

  83. 83.

    van Driel, M. & van Leeuwen, J. Vitamin D endocrinology of bone mineralization. Mol. Cell Endocrinol. 453, 46–51 (2017).

    PubMed  Google Scholar 

  84. 84.

    Woeckel, V. J. et al. 1α,25-(OH)2D3 acts in the early phase of osteoblast differentiation to enhance mineralization via accelerated production of mature matrix vesicles. J. Cell. Physiol. 225, 593–600 (2010).

    CAS  PubMed  Google Scholar 

  85. 85.

    Lin, E. L. et al. Healing of vitamin D deficiency rickets complicating hypophosphatasia suggests a role beyond circulating mineral sufficiency for vitamin D in musculoskeletal health. Bone 136, 115322 (2020).

    CAS  PubMed  Google Scholar 

  86. 86.

    Willems, B. A., Vermeer, C., Reutelingsperger, C. P. & Schurgers, L. J. The realm of vitamin K dependent proteins: shifting from coagulation toward calcification. Mol. Nutr. Food Res. 58, 1620–1635 (2014).

    CAS  PubMed  Google Scholar 

  87. 87.

    Zoch, M. L., Clemens, T. L. & Riddle, R. C. New insights into the biology of osteocalcin. Bone 82, 42–49 (2016).

    CAS  PubMed  Google Scholar 

  88. 88.

    Schurgers, L. J., Uitto, J. & Reutelingsperger, C. P. Vitamin K-dependent carboxylation of matrix Gla-protein: a crucial switch to control ectopic mineralization. Trends Mol. Med. 19, 217–226 (2013).

    CAS  PubMed  Google Scholar 

  89. 89.

    Theuwissen, E., Smit, E. & Vermeer, C. The role of vitamin K in soft-tissue calcification. Adv. Nutr. 3, 166–173 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Barrett, H., O’Keeffe, M., Kavanagh, E., Walsh, M. & O’Connor, E. M. Is matrix gla protein associated with vascular calcification? A systematic review. Nutrients 10, 415 (2018).

    PubMed Central  Google Scholar 

  91. 91.

    Nigwekar, S. U. et al. Vitamin K-dependent carboxylation of matrix gla protein influences the risk of calciphylaxis. J. Am. Soc. Nephrol. 28, 1717–1722 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Siltari, A. & Vapaatalo, H. Vascular calcification, vitamin K and warfarin therapy - possible or plausible connection? Basic. Clin. Pharmacol. Toxicol. 122, 19–24 (2018).

    CAS  PubMed  Google Scholar 

  93. 93.

    Tantisattamo, E., Han, K. H. & O’Neill, W. C. Increased vascular calcification in patients receiving warfarin. Arterioscler. Thromb. Vasc. Biol. 35, 237–242 (2015).

    CAS  PubMed  Google Scholar 

  94. 94.

    Win, T. T. et al. Apixaban versus warfarin in evaluation of progression of atherosclerotic and calcified plaques (prospective randomized trial). Am. Heart J. 212, 129–133 (2019).

    CAS  PubMed  Google Scholar 

  95. 95.

    Brandenburg, V. M. et al. Slower progress of aortic valve calcification with vitamin K supplementation: results from a prospective interventional proof-of-concept study. Circulation 135, 2081–2083 (2017).

    PubMed  Google Scholar 

  96. 96.

    Graham, A. & Richardson, J. Developmental and evolutionary origins of the pharyngeal apparatus. Evodevo 3, 24 (2012).

    PubMed  PubMed Central  Google Scholar 

  97. 97.

    Peissig, K., Condie, B. G. & Manley, N. R. Embryology of the parathyroid glands. Endocrinol. Metab. Clin. North Am. 47, 733–742 (2018).

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    Günther, T. et al. Genetic ablation of parathyroid glands reveals another source of parathyroid hormone. Nature 406, 199–203 (2000).

    PubMed  Google Scholar 

  99. 99.

    Ding, C., Buckingham, B. & Levine, M. A. Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB. J. Clin. Invest. 108, 1215–1220 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Mannstadt, M. et al. Dominant-negative GCMB mutations cause an autosomal dominant form of hypoparathyroidism. J. Clin. Endocrinol. Metab. 93, 3568–3576 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Bowl, M. R. et al. Identification and characterization of novel parathyroid-specific transcription factor Glial Cells Missing Homolog B (GCMB) mutations in eight families with autosomal recessive hypoparathyroidism. Hum. Mol. Genet. 19, 2028–2038 (2010).

    CAS  PubMed  Google Scholar 

  102. 102.

    Hannan, F. M., Kallay, E., Chang, W., Brandi, M. L. & Thakker, R. V. The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases. Nat. Rev. Endocrinol. 15, 33–51 (2018).

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Walker, M. D. & Silverberg, S. J. Primary hyperparathyroidism. Nat. Rev. Endocrinol. 14, 115–125 (2018).

    CAS  PubMed  Google Scholar 

  104. 104.

    Brewer, K., Costa-Guda, J. & Arnold, A. Molecular genetic insights into sporadic primary hyperparathyroidism. Endocr. Relat. Cancer 26, R53–R72 (2019).

    CAS  PubMed  Google Scholar 

  105. 105.

    Chandrasekharappa, S. C. et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276, 404–407 (1997).

    CAS  PubMed  Google Scholar 

  106. 106.

    Imanishi, Y. et al. Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin D1 in transgenic mice. J. Clin. Invest. 107, 1093–1102 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Mallya, S. M. et al. Abnormal parathyroid cell proliferation precedes biochemical abnormalities in a mouse model of primary hyperparathyroidism. Mol. Endocrinol. 19, 2603–2609 (2005).

    CAS  PubMed  Google Scholar 

  108. 108.

    Thakker, R. V. et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J. Clin. Endocrinol. Metab. 97, 2990–3011 (2012).

    CAS  PubMed  Google Scholar 

  109. 109.

    El-Hajj Fuleihan, G.& Arnold, A. Parathyroid carcinoma. UpToDate 14.0 (eds Drezner, M.K. & Mulder, J.E.) https://www.uptodate.com/contents/parathyroid-carcinoma (2021).

  110. 110.

    Insogna, K. L. Primary hyperparathyroidism. N. Engl. J. Med. 379, 1050–1059 (2018).

    PubMed  Google Scholar 

  111. 111.

    Bilezikian, J. P., Bandeira, L., Khan, A. & Cusano, N. E. Hyperparathyroidism. Lancet 391, 168–178 (2018).

    CAS  PubMed  Google Scholar 

  112. 112.

    Minisola, S., Gianotti, L., Bhadada, S. & Silverberg, S. J. Classical complications of primary hyperparathyroidism. Best Pract. Res. Clin. Endocrinol. Metab. 32, 791–803 (2018).

    PubMed  Google Scholar 

  113. 113.

    Khan, A. A. et al. Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus. Osteoporos. Int. 28, 1–19 (2017).

    CAS  PubMed  Google Scholar 

  114. 114.

    Clarke, B. L. et al. Epidemiology and diagnosis of hypoparathyroidism. J. Clin. Endocrinol. Metab. 101, 2284–2299 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Hoogendam, J. et al. Novel mutations in the parathyroid hormone (PTH)/PTH-related peptide receptor type 1 causing Blomstrand osteochondrodysplasia types I and II. J. Clin. Endocrinol. Metab. 92, 1088–1095 (2007).

    CAS  PubMed  Google Scholar 

  116. 116.

    Langdahl, B. L., Mortensen, L., Vesterby, A., Eriksen, E. F. & Charles, P. Bone histomorphometry in hypoparathyroid patients treated with vitamin D. Bone 18, 103–108 (1996).

    CAS  PubMed  Google Scholar 

  117. 117.

    Rubin, M. R. et al. Dynamic and structural properties of the skeleton in hypoparathyroidism. J. Bone Min. Res. 23, 2018–2024 (2008).

    CAS  Google Scholar 

  118. 118.

    Rubin, M. R. et al. PTH(1-84) administration reverses abnormal bone-remodeling dynamics and structure in hypoparathyroidism. J. Bone Min. Res. 26, 2727–2736 (2011).

    CAS  Google Scholar 

  119. 119.

    Cusano, N. E. et al. Changes in skeletal microstructure through four continuous years of rhPTH(1-84) therapy in hypoparathyroidism. J. Bone Min. Res. 35, 1274–1281 (2020).

    CAS  Google Scholar 

  120. 120.

    Kovacs, C. S. Bone development and mineral homeostasis in the fetus and neonate: roles of the calciotropic and phosphotropic hormones. Physiol. Rev. 94, 1143–1218 (2014).

    CAS  PubMed  Google Scholar 

  121. 121.

    Kovacs, C. S. & Ward, L. E. In Maternal-Fetal and Neonatal Endocrinology: Physiology, Pathophysiology, and Clinical Management (eds Kovacs, C. S. & Deal, C. L.) 573–586 (Academic Press, 2019).

  122. 122.

    Kovacs, C. S. et al. Regulation of murine fetal-placental calcium metabolism by the calcium-sensing receptor. J. Clin. Invest. 101, 2812–2820 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Kovacs, C. S., Manley, N. R., Moseley, J. M., Martin, T. J. & Kronenberg, H. M. Fetal parathyroids are not required to maintain placental calcium transport. J. Clin. Invest. 107, 1007–1015 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Kovacs, C. S., Chafe, L. L., Fudge, N. J., Friel, J. K. & Manley, N. R. PTH regulates fetal blood calcium and skeletal mineralization independently of PTHrP. Endocrinology 142, 4983–4993 (2001).

    CAS  PubMed  Google Scholar 

  125. 125.

    Simmonds, C. S., Karsenty, G., Karaplis, A. C. & Kovacs, C. S. Parathyroid hormone regulates fetal-placental mineral homeostasis. J. Bone Min. Res. 25, 594–605 (2010).

    CAS  Google Scholar 

  126. 126.

    Miao, D., He, B., Karaplis, A. C. & Goltzman, D. Parathyroid hormone is essential for normal fetal bone formation. J. Clin. Invest. 109, 1173–1182 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Halloran, B. P. & De Luca, H. F. Effect of vitamin D deficiency on skeletal development during early growth in the rat. Arch. Biochem. Biophys. 209, 7–14 (1981).

    CAS  PubMed  Google Scholar 

  128. 128.

    Miller, S. C., Halloran, B. P., DeLuca, H. F. & Jee, W. S. Studies on the role of vitamin D in early skeletal development, mineralization, and growth in rats. Calcif. Tissue Int. 35, 455–460 (1983).

    CAS  PubMed  Google Scholar 

  129. 129.

    Brommage, R. & DeLuca, H. F. Placental transport of calcium and phosphorus is not regulated by vitamin D. Am. J. Physiol. 246, F526–529 (1984).

    CAS  PubMed  Google Scholar 

  130. 130.

    Glazier, J. D., Mawer, E. B. & Sibley, C. P. Calbindin-D9K gene expression in rat chorioallantoic placenta is not regulated by 1,25-dihydroxyvitamin D3. Pediatr. Res. 37, 720–725 (1995).

    CAS  PubMed  Google Scholar 

  131. 131.

    Kovacs, C. S. Maternal mineral and bone metabolism during pregnancy, lactation, and post-weaning recovery. Physiol. Rev. 96, 449–547 (2016).

    CAS  PubMed  Google Scholar 

  132. 132.

    Roth, D. E. et al. Vitamin D supplementation in pregnancy and lactation and infant growth. N. Engl. J. Med. 379, 535–546 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Roth, D. E. et al. Vitamin D supplementation during pregnancy: state of the evidence from a systematic review of randomised trials. Br. Med. J. 359, j5237 (2017).

    Google Scholar 

  134. 134.

    Ryan, B. A. et al. Complete absence of calcitriol in Cyp27b1 null fetal mice does not disturb mineral metabolism or skeletal development. J. Bone Min. Res. 32, S320 (2017).

    Google Scholar 

  135. 135.

    Lachenmaier-Currle, U., Breves, G. & Harmeyer, J. Role of 1,25-(OH)2D3 during pregnancy; studies with pigs suffering from pseudo-vitamin D-deficiency rickets, type I. Q. J. Exp. Physiol. 74, 875–881 (1989).

    CAS  PubMed  Google Scholar 

  136. 136.

    Lachenmaier-Currle, U. & Harmeyer, J. Placental transport of calcium and phosphorus in pigs. J. Perinat. Med. 17, 127–136 (1989).

    CAS  PubMed  Google Scholar 

  137. 137.

    Kovacs, C. S., Woodland, M. L., Fudge, N. J. & Friel, J. K. The vitamin D receptor is not required for fetal mineral homeostasis or for the regulation of placental calcium transfer in mice. Am. J. Physiol. Endocrinol. Metab. 289, E133–E144 (2005).

    CAS  PubMed  Google Scholar 

  138. 138.

    Lieben, L., Stockmans, I., Moermans, K. & Carmeliet, G. Maternal hypervitaminosis D reduces fetal bone mass and mineral acquisition and leads to neonatal lethality. Bone 57, 123–131 (2013).

    CAS  PubMed  Google Scholar 

  139. 139.

    Ma, Y. et al. Neither absence nor excess of FGF23 disturbs murine fetal-placental phosphorus homeostasis or prenatal skeletal development and mineralization. Endocrinology 155, 1596–1605 (2014).

    PubMed  PubMed Central  Google Scholar 

  140. 140.

    Ma, Y. et al. FGF23 is not required to regulate fetal phosphorus metabolism but exerts effects within 12 hours after birth. Endocrinology 158, 252–263 (2017).

    CAS  PubMed  Google Scholar 

  141. 141.

    Ohata, Y. et al. Elevated fibroblast growth factor 23 exerts its effects on placenta and regulates vitamin D metabolism in pregnancy of Hyp mice. J. Bone Min. Res. 29, 1627–1638 (2014).

    CAS  Google Scholar 

  142. 142.

    Karaplis, A. C. et al. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev. 8, 277–289 (1994).

    CAS  PubMed  Google Scholar 

  143. 143.

    Kovacs, C. S. et al. Parathyroid hormone-related peptide (PTHrP) regulates fetal-placental calcium transport through a receptor distinct from the PTH/PTHrP receptor. Proc. Natl Acad. Sci. USA 93, 15233–15238 (1996).

    CAS  PubMed  Google Scholar 

  144. 144.

    Lanske, B. et al. PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273, 663–666 (1996).

    CAS  PubMed  Google Scholar 

  145. 145.

    Abbas, S. K. et al. Stimulation of ovine placental calcium transport by purified natural and recombinant parathyroid hormone-related protein (PTHrP) preparations. Q. J. Exp. Physiol. 74, 549–552 (1989).

    CAS  PubMed  Google Scholar 

  146. 146.

    Wu, T. L. et al. Structural and physiologic characterization of the mid-region secretory species of parathyroid hormone-related protein. J. Biol. Chem. 271, 24371–24381 (1996).

    CAS  PubMed  Google Scholar 

  147. 147.

    Loughead, J. L., Mimouni, F. & Tsang, R. C. Serum ionized calcium concentrations in normal neonates. Am. J. Dis. Child. 142, 516–518 (1988).

    CAS  PubMed  Google Scholar 

  148. 148.

    David, L. & Anast, C. S. Calcium metabolism in newborn infants. The interrelationship of parathyroid function and calcium, magnesium, and phosphorus metabolism in normal, “sick,” and hypocalcemic newborns. J. Clin. Invest. 54, 287–296 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Schauberger, C. W. & Pitkin, R. M. Maternal-perinatal calcium relationships. Obstet. Gynecol. 53, 74–76 (1979).

    CAS  PubMed  Google Scholar 

  150. 150.

    Kovacs, C. S. & Ward, L. E. in Maternal-Fetal and Neonatal Endocrinology: Physiology, Pathophysiology, and Clinical Management (eds Kovacs, C. S. & Deal, C. S.) 755–782 (Academic Press, 2019).

  151. 151.

    Kovacs, C. S. Bone metabolism in the fetus and neonate. Pediatr. Nephrol. 29, 793–803 (2014).

    PubMed  Google Scholar 

  152. 152.

    Suzuki, Y. et al. Calcium channel TRPV6 is involved in murine maternal-fetal calcium transport. J. Bone Min. Res. 23, 1249–1256 (2008).

    CAS  Google Scholar 

  153. 153.

    Hunt, C. D. & Johnson, L. K. Calcium requirements: new estimations for men and women by cross-sectional statistical analyses of calcium balance data from metabolic studies. Am. J. Clin. Nutr. 86, 1054–1063 (2007).

    CAS  PubMed  Google Scholar 

  154. 154.

    Kovacs, C. S. In Maternal-Fetal and Neonatal Endocrinology: Physiology, Pathophysiology, and Clinical Management (eds Kovacs, C.S. & Deal, C.S.) 61–73 (Academic Press, 2019).

  155. 155.

    Gillies, B. R. et al. Absence of calcitriol causes increased lactational bone loss and lower milk calcium but does not impair post-lactation bone recovery in Cyp27b1 null mice. J. Bone Min. Res. 33, 16–26 (2018).

    CAS  Google Scholar 

  156. 156.

    Fudge, N. J. & Kovacs, C. S. Pregnancy up-regulates intestinal calcium absorption and skeletal mineralization independently of the vitamin D receptor. Endocrinology 151, 886–895 (2010).

    CAS  PubMed  Google Scholar 

  157. 157.

    Halloran, B. P. & DeLuca, H. F. Calcium transport in small intestine during pregnancy and lactation. Am. J. Physiol. 239, E64–68 (1980).

    CAS  PubMed  Google Scholar 

  158. 158.

    Brommage, R., Baxter, D. C. & Gierke, L. W. Vitamin D-independent intestinal calcium and phosphorus absorption during reproduction. Am. J. Physiol. 259, G631–G638 (1990).

    CAS  PubMed  Google Scholar 

  159. 159.

    Purdie, D. W., Aaron, J. E. & Selby, P. L. Bone histology and mineral homeostasis in human pregnancy. Br. J. Obstet. Gynaecol. 95, 849–854 (1988).

    CAS  PubMed  Google Scholar 

  160. 160.

    Moller, U. K., Vieth Streym, S., Mosekilde, L. & Rejnmark, L. Changes in bone mineral density and body composition during pregnancy and postpartum. A controlled cohort study. Osteoporos. Int. 23, 1213–1223 (2012).

    CAS  PubMed  Google Scholar 

  161. 161.

    Ó Breasail, M., Prentice, A. & Ward, K. Pregnancy-related bone mineral and microarchitecture changes in women aged 30 to 45 years. J. Bone Min. Res. 35, 1253–1262 (2020).

    Google Scholar 

  162. 162.

    Kovacs, C. S. & Ralston, S. H. Presentation and management of osteoporosis presenting in association with pregnancy or lactation. Osteoporos. Int. 26, 2223–2241 (2015).

    CAS  PubMed  Google Scholar 

  163. 163.

    Kalkwarf, H. J., Specker, B. L., Bianchi, D. C., Ranz, J. & Ho, M. The effect of calcium supplementation on bone density during lactation and after weaning. N. Engl. J. Med. 337, 523–528 (1997).

    CAS  PubMed  Google Scholar 

  164. 164.

    Cross, N. A., Hillman, L. S., Allen, S. H. & Krause, G. F. Changes in bone mineral density and markers of bone remodeling during lactation and postweaning in women consuming high amounts of calcium. J. Bone Min. Res. 10, 1312–1320 (1995).

    CAS  Google Scholar 

  165. 165.

    Polatti, F., Capuzzo, E., Viazzo, F., Colleoni, R. & Klersy, C. Bone mineral changes during and after lactation. Obstet. Gynecol. 94, 52–56 (1999).

    CAS  PubMed  Google Scholar 

  166. 166.

    Kovacs, C. S., Chakhtoura, M. & El-Hajj Fuleihan, G. In Maternal-Fetal and Neonatal Endocrinology Physiology, Pathophysiology, and Clinical Management (eds Kovacs, C. S. & Deal, C. S.) 329–370 (Academic Press, 2019).

  167. 167.

    Brembeck, P., Lorentzon, M., Ohlsson, C., Winkvist, A. & Augustin, H. Changes in cortical volumetric bone mineral density and thickness, and trabecular thickness in lactating women postpartum. J. Clin. Endocrinol. Metab. 100, 535–543 (2015).

    CAS  PubMed  Google Scholar 

  168. 168.

    Bjornerem, A. et al. Irreversible deterioration of cortical and trabecular microstructure associated with breastfeeding. J. Bone Min. Res. 32, 681–687 (2017).

    Google Scholar 

  169. 169.

    Ryan, B. A. & Kovacs, C. S. The puzzle of lactational bone physiology: osteocytes masquerade as osteoclasts and osteoblasts. J. Clin. Invest. 129, 3041–3044 (2019).

    PubMed  PubMed Central  Google Scholar 

  170. 170.

    Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D (National Academies Press, 2011).

  171. 171.

    Ross, A. C. et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J. Clin. Endocrinol. Metab. 96, 53–58 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Kovacs, C. S. In Principles of Endocrinology and Hormone Action (eds Belfiore, A. & Le Roith, D.) 367–386 (Springer, 2016).

  173. 173.

    Ryan, B. A. & Kovacs, C. S. Calciotropic and phosphotropic hormones in fetal and neonatal bone development. Semin. Fetal Neonatal Med. 25, 101062 (2020).

    PubMed  Google Scholar 

Download references

Acknowledgements

The Menarini Foundation (Fondazione Internazionale Menarini) supported the conference in Florence, Italy, on Biomineralization in Health and Disease, which served as impetus and inspiration for this article. The authors acknowledge the support of the Murray–Heilig Fund in Molecular Medicine (A.A.); Canadian Institutes of Health Research (C.S.K.); Fondazione Italiana Ricerca sulle Malattie dell’Osso (M.L.B.); Wellcome Trust Investigator Award, National Institute for Health Research (NIHR) Senior Investigator Award, and NIHR Oxford Biomedical Research Centre Programme (R.V.T.).

Author information

Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Andrew Arnold.

Ethics declarations

Competing interests

R.R. has received fees for advisory board or lectures from Abiogen, CNIEL, Danone, Echolight, EMF, Mithra, Mylan, Nestlé, ObsEva, Pfizer Consumer Health, Radius Health, Rejuvenate, Sandoz and Theramex. The other authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Endocrinology thanks R. Kuma, J. Lian and A. Martin for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Tetrapod transition

The water-to-land transition, involving evolutionary adaptations such as four legs and joints that enabled walking on land.

Calcium–PTH setpoint

Refers to the relationship between extracellular calcium concentration and parathyroid hormone (PTH) release. Setpoint is the calcium concentration at which PTH release (or circulating concentration) is mid-way between its maximum and minimum values.

Multiple endocrine neoplasia type 1

(MEN1). A disorder characterized by predisposition to primary hyperparathyroidism in association with neuroendocrine tumours of the pancreas, pituitary adenomas and adrenal tumours.

Albright’s hereditary osteodystrophy

(AHO). A genetic syndrome characterized by short stature, obesity, subcutaneous calcification, mental retardation, round face, dental hypoplasia and brachydactyly.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Arnold, A., Dennison, E., Kovacs, C.S. et al. Hormonal regulation of biomineralization. Nat Rev Endocrinol 17, 261–275 (2021). https://doi.org/10.1038/s41574-021-00477-2

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing