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Regulation of FGF23 production and phosphate metabolism by bone–kidney interactions

Nature Reviews Nephrology volume 19, pages 185–193 (2023)Cite this article

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Abstract

The bone-derived hormone fibroblast growth factor 23 (FGF23) functions in concert with parathyroid hormone (PTH) and the active vitamin D metabolite, 1,25(OH)2 vitamin D (1,25D), to control phosphate and calcium homeostasis. A rise in circulating levels of phosphate and 1,25D leads to FGF23 production in bone. Circulating FGF23 acts on the kidney by binding to FGF receptors and the co-receptor α-Klotho to promote phosphaturia and reduce circulating 1,25D levels. Various other biomolecules that are produced by the kidney, including lipocalin-2, glycerol 3-phosphate, 1-acyl lysophosphatidic acid and erythropoietin, are involved in the regulation of mineral metabolism via effects on FGF23 synthesis in bone. Understanding of the molecular mechanisms that control FGF23 synthesis in the bone and its bioactivity in the kidney has led to the identification of potential targets for novel interventions. Emerging approaches to target aberrant phosphate metabolism include small molecule inhibitors that directly bind FGF23 and prevent its interactions with FGF receptors and α-Klotho, FGF23 peptide fragments that act as competitive inhibitors of intact FGF23 and small molecule inhibitors of kidney sodium-phosphate cotransporters.

Key points

  • The osteocyte-derived hormone fibroblast growth factor 23 (FGF23) controls renal handling of phosphate and active 1,25(OH)2 vitamin D(1,25D).

  • Rare heritable and common acquired disturbances in FGF23 homeostasis, including chronic kidney disease, are associated with altered mineral balance.

  • The regulation of FGF23 production in osteocytes occurs via transcriptional and post-translational mechanisms.

  • In the kidney, binding of FGF23 to its co-receptor α-Klotho and fibroblast growth factor receptors results in a reduction in blood phosphate and inhibits the production of 1,25D.

  • The kidney-derived factors glycerol-3-phophate/1-acyl lysophosphatidic acid, lipocalin-2 and erythropoietin stimulate bone FGF23 synthesis.

  • Identification of the mechanisms of FGF23 functions and the effects of FGF23 on downstream targets in the kidney could lead to the development of novel therapeutics.

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Fig. 1: Kidney–bone crosstalk.
Fig. 2: Potential approaches to modulating FGF23 bioactivity.

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Acknowledgements

The authors acknowledge NIH grants R21-AR059278, R01-DK112958, and R01-HL145528 (K.E.W); The David Weaver Professorship (K.E.W); and NIDDK-K99/R00 DK129705 (R.A.).

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  1. Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Rafiou Agoro & Kenneth E. White

  2. Department of Medicine, Division of Nephrology, Indiana University School of Medicine, 46202, Indianapolis, IN, USA

    Kenneth E. White

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

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Correspondence to Kenneth E. White.

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K.E.W. receives royalties for licensing FGF23 to Kyowa Hakko Kirin Co., Ltd., has previously received funding from Akebia and currently receives funding from Calico Labs. K.E.W. also owns equity interest in FGF Therapeutics. R.A. has no competing interests.

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Agoro, R., White, K.E. Regulation of FGF23 production and phosphate metabolism by bone–kidney interactions. Nat Rev Nephrol 19, 185–193 (2023). https://doi.org/10.1038/s41581-022-00665-x

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