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  • Review Article
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Hormonal regulation of biomineralization

Nature Reviews Endocrinology volume 17, pages 261–275 (2021)Cite this article

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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.

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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.

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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.).

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Authors and Affiliations

  1. Division of Endocrinology & Metabolism and Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, CT, USA

    Andrew Arnold

  2. MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK

    Elaine Dennison

  3. Faculty of Medicine – Endocrinology, Memorial University of Newfoundland, St. John’s, NL, Canada

    Christopher S. Kovacs

  4. Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Michael Mannstadt

  5. Division of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland

    René Rizzoli

  6. Department of Biochemical, Experimental and Clinical Sciences, University of Florence, Florence, Italy

    Maria Luisa Brandi

  7. Mayo Clinic Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Rochester, MN, USA

    Bart Clarke

  8. Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    Rajesh V. Thakker

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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.

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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.

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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

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