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FGF23 at the crossroads of phosphate, iron economy and erythropoiesis

Nature Reviews Nephrology volume 16, pages 7–19 (2020)Cite this article

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Abstract

Fibroblast growth factor 23 (FGF23) was initially characterized as an important regulator of phosphate and calcium homeostasis. New research advances demonstrate that FGF23 is also linked to iron economy, inflammation and erythropoiesis. These advances have been fuelled, in part, by the serendipitous development of two distinct FGF23 assays that can substitute for invasive bone biopsies to infer the activity of the three main steps of FGF23 regulation in bone: transcription, post-translational modification and peptide cleavage. This ‘liquid bone biopsy for FGF23 dynamics’ enables large-scale longitudinal studies of FGF23 regulation that would otherwise be impossible in humans. The balance between FGF23 production, post-translational modification and cleavage is maintained or perturbed in different hereditary monogenic conditions and in acquired conditions that mimic these genetic disorders, including iron deficiency, inflammation, treatment with ferric carboxymaltose and chronic kidney disease. Looking ahead, a deeper understanding of the relationships between FGF23 regulation, iron homeostasis and erythropoiesis can be leveraged to devise novel therapeutic targets for treatment of anaemia and states of FGF23 excess, including chronic kidney disease.

Key points

  • The development of two complementary assays of full-length and C-terminal FGF23 provided tools to non-invasively survey FGF23 transcription and cleavage.

  • Iron deficiency, inflammation and erythropoiesis stimulate simultaneous production and cleavage of FGF23. This coupling of FGF23 transcription and FGF23 cleavage results in minimal change in concentrations of biologically active FGF23.

  • Albeit through different mechanisms, autosomal dominant hypophosphataemic rickets, chronic kidney disease and administration of ferric carboxymaltose reduce FGF23 cleavage. Uncoupling FGF23 protein cleavage from FGF23 gene transcription results in elevated concentrations of biologically active FGF23.

  • In individuals with normal kidney function, states of uncoupled FGF23 transcription and cleavage can lead to severe hypophosphataemia owing to the phosphaturic and vitamin D-suppressing effects of the increased levels of biologically active FGF23.

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Fig. 1: FGF23 production, cleavage and serological assays.
Fig. 2: ‘Liquid bone biopsy for FGF23 dynamics’.
Fig. 3: Pathways linking inflammation and FGF23 regulation.
Fig. 4: Hypoxia-inducible factors in the regulation of FGF23.
Fig. 5: Interrelationships among iron deficiency, intravenous iron administration, FGF23 and mineral homeostasis.

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Authors and Affiliations

  1. Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA

    Daniel Edmonston & Myles Wolf

  2. Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA

    Daniel Edmonston & Myles Wolf

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Both authors researched data for the article, made substantial contributions to discussions of the content, and wrote, reviewed and edited the manuscript before submission.

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Glossary

Phosphatonin

A collective term for phosphate-regulating factors, including FGF23.

Vitamin D-resistant hypophosphataemic rickets

A class of diseases characterized by low serum phosphate, rickets and resistance to treatment with vitamin D.

Tumour-induced osteomalacia

(TIO). A disease caused by extraosseous FGF23 production by tumour cells, which results in severe hypophosphataemia and osteomalacia.

Iron economy

Regulation of serum iron levels and total body iron stores.

Autosomal dominant hypophosphatemic rickets

(ADHR). An inherited form of hypophosphataemic rickets caused by a mutation in the FGF23 cleavage recognition site, which results in excess FGF23 due to impaired cleavage.

Absorption

The transport of nutrients, including phosphate and calcium, from the intestinal lumen into circulation.

Tumoural calcinosis

A disease caused by a mutation in GALNT3, which results in excess FGF23 cleavage, functional FGF23 deficiency, hyperphosphataemia and diffuse metastatic calcification.

Autosomal recessive hypophosphataemic rickets

(ARHR). An inherited form of hypophosphataemic rickets that can be caused by mutations in the DMP1 gene (type 1) or the ENPP1 gene (type 2), which results in FGF23 excess.

Acute-phase reactant

A circulating factor that increases in response to inflammation.

Resorption

Degradation of bone that releases calcium and phosphate into the circulation.

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Edmonston, D., Wolf, M. FGF23 at the crossroads of phosphate, iron economy and erythropoiesis. Nat Rev Nephrol 16, 7–19 (2020). https://doi.org/10.1038/s41581-019-0189-5

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