Abstract
The discovery of fibroblast growth factor 23 (FGF-23) has expanded our understanding of phosphate and vitamin D homeostasis and provided new insights into the pathogenesis of hereditary hypophosphatemic and hyperphosphatemic disorders, as well as acquired disorders of phosphate metabolism, such as chronic kidney disease. FGF-23 is secreted by osteoblasts and osteocytes in bone and principally targets the kidney to regulate the reabsorption of phosphate, the production and catabolism of 1,25-dihydroxyvitamin D and the expression of α-Klotho, an anti-ageing hormone. Secreted FGF-23 plays a central role in complex endocrine networks involving local bone-derived factors that regulate mineralization of extracellular matrix and systemic hormones involved in mineral metabolism. Inactivating mutations of PHEX, DMP1 and ENPP1, which cause hereditary hypophosphatemic disorders and primary defects in bone mineralization, stimulate FGF23 gene transcription in osteoblasts and osteocytes, at least in part, through canonical and intracrine FGF receptor pathways. These FGF-23 regulatory pathways may enable systemic phosphate and vitamin D homeostasis to be coordinated with bone mineralization. FGF-23 also functions as a counter-regulatory hormone for 1,25-dihydroxyvitamin D in a bone–kidney endocrine loop. FGF-23, through regulation of additional genes in the kidney and extrarenal tissues, probably has broader physiological functions beyond regulation of mineral metabolism that account for the association between FGF-23 and increased mortality and morbidity in chronic kidney disease.
Key Points
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FGF-23 is a hormone produced by osteoblasts and osteocytes in bone that causes phosphaturia and inhibits 1,25-dihydroxyvitamin D production through its binding to FGFR–α-Klotho complexes in kidney tubules
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Primary elevations of circulating FGF-23 concentrations cause hereditary hypophosphatemic disorders and acquired hypophosphatemic disorders, and reductions in circulating FGF-23 concentrations cause familial tumoral calcinosis
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FGF-23 is regulated by local bone-derived factors through activation of FGFR-1 pathways and by systemic factors, including 1,25-dihydroxyvitamin D and parathyroid hormone (in a context-dependent fashion) in osteoblasts
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FGF-23 participates in several physiologically relevant endocrine axes involving 1,25-dihydroxyvitamin D or parathyroid hormone, and possibly additional hormonal networks involving secreted α-Klotho and other kidney-derived factors
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Elevations in serum FGF-23 is an early adaptive response in chronic kidney disease, leading to maintenance of phosphate balance and development of secondary hyperparathryroidism through reductions in 1,25-dihydroxyvitamin D levels
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Elevations of circulating FGF-23 are an unexpectedly strong predictor of mortality in patients with renal failure, as a result of mechanisms that remain to be elucidated
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Quarles, L. Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism. Nat Rev Endocrinol 8, 276–286 (2012). https://doi.org/10.1038/nrendo.2011.218
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DOI: https://doi.org/10.1038/nrendo.2011.218
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