Role of phosphate sensing in bone and mineral metabolism

Abstract

Inorganic phosphate (Pi) is essential for signal transduction and cell metabolism, and is also an essential structural component of the extracellular matrix of the skeleton. Pi is sensed in bacteria and yeast at the plasma membrane, which activates intracellular signal transduction to control the expression of Pi transporters and other genes that control intracellular Pi levels. In multicellular organisms, Pi homeostasis must be maintained in the organism and at the cellular level, requiring an endocrine and metabolic Pi-sensing mechanism, about which little is currently known. This Review will discuss the metabolic effects of Pi, which are mediated by Pi transporters, inositol pyrophosphates and SYG1–Pho81–XPR1 (SPX)-domain proteins to maintain cellular phosphate homeostasis in the musculoskeletal system. In addition, we will discuss how Pi is sensed by the human body to regulate the production of fibroblast growth factor 23 (FGF23), parathyroid hormone and calcitriol to maintain serum levels of Pi in a narrow range. New findings on the crosstalk between iron and Pi homeostasis in the regulation of FGF23 expression will also be outlined. Mutations in components of these metabolic and endocrine phosphate sensors result in genetic disorders of phosphate homeostasis, cardiomyopathy and familial basal ganglial calcifications, highlighting the importance of this newly emerging area of research.

Key points

  • Endocrine regulation of gastrointestinal absorption, storage in the mineral deposits of the skeleton and renal excretion of inorganic phosphate (Pi) maintains the serum concentration of Pi within a narrow range.

  • Pi activates extracellular-signal-regulated kinases 1 and 2 in mammalian cells, which are required for stimulation of mitochondrial respiration and transcription of bone matrix proteins.

  • Pi stimulates the synthesis and secretion of parathyroid hormone and fibroblast growth factor 23 and blocks the synthesis of calcitriol; however, the endocrine sensor for Pi remains unknown.

  • Mutations in the endocrine regulators of Pi lead to genetic disorders characterized by abnormal bone and mineral metabolism and ectopic calcifications.

  • Identification of loss-of-function mutations in several Pi transporters highlights the importance of intracellular Pi for muscle function and vascular calcifications.

  • How intracellular Pi causes myopathy, tumour formation and changes associated with acclerated ageing is less well understood.

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Fig. 1: Pi sensing pathways.
Fig. 2: Regulation of bone cell function and matrix mineralization by Pi.
Fig. 3: Endocrine regulation of Pi homeostasis.
Fig. 4: Diseases of phosphate homeostasis organized by organ system.

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Acknowledgements

C.B. is supported by the Yale O’Brien Center (P30DK079310), and S.C. is supported by a postdoctoral fellowship from the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (T32DK007058-42).

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Both authors researched the data for the article, provided substantial contribution to the discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Clemens Bergwitz.

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Glossary

Phosphaturic hormone

Hormone causing excretion of phosphate in the urine.

Hypomorphic alleles

Genes that have a mutation that causes a partial loss of gene function.

Haploinsufficiency

Refers to complete loss of function of one copy of a gene when the remaining functional copy of the gene is not adequate to produce the needed gene product to preserve normal function.

5/6 nephrectomy

Model of progressive renal failure with reduced nephron number achieved by either infarction or surgical excision of both poles and removal of the contralateral kidney.

Pulmonary alveolar microlithiasis

A rare autosomal recessive disease of widespread intra-alveolar accumulation of minute calcium phosphate calculi called microliths caused by homozygous loss-of-function mutations in SLC34A2 (which encodes NPT2b).

Tumoural calcinosis

Group of rare autosomal recessive metabolic disorders characterized by the development of severe ectopic calcifications in soft tissues due to homozygous loss-of-function mutations in the GALNT3, FGF23 or KL genes.

Osteomalacia

Osteomalacia is a rare disorder of bone metabolism leading to reduced bone matrix mineralization.

Phosphatonins

Phosphatonins is the collective term used for major regulators of Pi homeostasis, which generally function as phosphaturic hormones and lower blood levels of Pi.

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Chande, S., Bergwitz, C. Role of phosphate sensing in bone and mineral metabolism. Nat Rev Endocrinol 14, 637–655 (2018). https://doi.org/10.1038/s41574-018-0076-3

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