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Phosphate-sensing and regulatory mechanism of FGF23 production

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Abstract

Background

Inorganic phosphate (Pi) is an essential mineral for human. Hypophosphatemia and hyperphosphatemia cause rickets/osteomalacia and ectopic calcification, respectively, indicating that serum Pi level needs to be regulated. Fibroblast growth factor (FGF) 23 is a principal hormone to regulate serum Pi level. FGF23 is produced by the bone, especially by the osteoblasts and osteocytes, and works by binding to FGF receptor (FGFR) 1c and α-Klotho complex in the kidney. FGF23 reduces serum Pi level by inhibiting both renal phosphate reabsorption and intestinal phosphate absorption via reduction of serum 1,25-dihydroxyvitamin D level. It has been unclear how the bone senses changes of serum Pi level and how the bone regulates the production of FGF23.

Recent findings

Our recent results indicate that the post-translational modification of FGF23 protein through a gene product of GALNT3 is the main regulatory mechanism of enhanced FGF23 production by high dietary Pi. Furthermore, high extracellular Pi directly activates FGFR1 and its downstream intracellular signaling pathway regulates the expression level of GALNT3.

Conclusions

We propose that FGFR1 works as a Pi-sensing receptor in the regulation of FGF23 production and serum Pi level. There is a negative feedback system, which is a basic mechanism of endocrine regulation, in the regulation of serum Pi involving FGFR1, and FGF23. These findings may lead to the development of new therapeutic methods to treat diseases caused by abnormal Pi level.

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Acknowledgements

This work was supported in part by Grant-in-Aid for Young Scientists from Japan Society for the Promotion of Science (18K15980) (to Y.T.) and by Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science (19H03676) (to S.F.).

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Authors and Affiliations

  1. Department of Endocrinology and Diabetes Mellitus, Fukuoka University Chikushi Hospital, Fukuoka, Japan

    Y. Takashi

  2. Department of Molecular Endocrinology, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan

    S. Fukumoto

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Y.T. wrote the manuscript and S.F. supervised the work.

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Correspondence to S. Fukumoto.

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Takashi, Y., Fukumoto, S. Phosphate-sensing and regulatory mechanism of FGF23 production. J Endocrinol Invest 43, 877–883 (2020). https://doi.org/10.1007/s40618-020-01205-9

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