Role of FGF23 in vitamin D and phosphate metabolism: implications in chronic kidney disease

Abstract

FGF23 is a bone-derived hormone that regulates systemic phosphate homeostasis, vitamin D metabolism and α-Klotho expression through a novel bone-kidney axis. FGF23 inhibits renal tubular reabsorption of phosphate through mechanisms independent of PTH as well as reduces circulating 1, 25(OH)(2)D through its dual effects to suppress Cyp27b1 production and to stimulate Cyp24 catabolism of 1,25(OH)(2)D. 1,25(OH)(2)D and other factors regulating bone remodeling/mineralization are the major physiological regulators of FGF23 expression. FGF23 also suppresses the gene transcription of α-klotho by the kidney, which exists as a membrane and soluble protein. Membrane Klotho acts as a coreceptor for and dictates organ specificity of FGF23, whereas soluble Klotho act as an endocrine factor that regulates activity of cell surface glycoproteins and receptors in multiple tissues. Elevated FGF23 levels are responsible for several hereditary and acquired hypophosphatemic rickets disorders. FGF23 and Klotho deficiency have similar phenotypes characterized by hyperphosphatemia, elevated 1,25(OH)(2)D and tumoral calcinosis. FGF23 levels progressively increase during chronic kidney disease (CKD). FGF23 has been proposed to be the initial adaptive response leading to reductions in 1,25(OH)(2)D and secondary hyperparathyroidism (HPT) in CKD. The overall biological effect of this initial step may be to orchestrate a coordinated adaptation to protect the organism from the adverse effects of excess phosphate retention. The second step involves the effects of PTH on bone remodeling that further stimulates FGF23 production through both direct and indirect mechanisms related to alterations in extracellular matrix factors. PTH further amplifies FGF23 expression in later stages of CKD to compensate for the increased phosphate efflux from bone caused by excessive bone turnover. While many aspects of the regulation and functions of FGF23 remain to be established, the idea that FGF23 hormone is the initial adaptive hormonal response in CKD that suppresses 1,25(OH)(2)D, reduces gastrointestinal calcium and phosphate absorption and leads to a secondary HPT represents a paradigm shift in the conceptualization of the pathogenesis of secondary hyperparathyroidism. In addition, the prevalent thought that CKD is a functional "vitamin D deficient state" requiring therapy with 1,25(OH)(2)D analogs is challenged by effects of FGF23 to potentially lower both 25(OH)D and 1,25(OH)D by induction of Cyp24-mediated degradation. Finally, increments in FGF23 are associated with increased cardiovascular mortality in CKD. Whether these effects represent direct effects of FGF23 or represent a marker of other abnormalities in CKD remains to be determined.

Figure 1

Integrative physiology of FGF23. FGF23 can exert multiple direct and indirect effects on a wide range of biological functions and is involved in complex endocrine networks involving 1,25(OH)₂D, Klotho, and PTH endocrine factors. FGF23 participates in a bone-kidney axis to regulate 1,25(OH)₂ D production and renal phosphate handling. FGF23 is regulated by 1,25(OH)₂D, which creates an endocrine loop between FGF23 and 1,25(OH)₂D. In addition, FGF23 regulates gene expression of Klotho, a transmembrane co-receptor for FGF23. Klotho is secreted by ectodomain shedding and by alternatively splicing and acts as a circulating hormone that regulates ion channels and function of receptors in multiple tissues. FGF23 expression in bone is also regulated by local intrinsic bone-derived factors that link FGF23 to bone mineralization and bone turnover, thereby linking bone phosphate buffering capacity with the renal handling of phosphate. PTH also stimulates FGF23 in a context dependent fashion that is modulated by the vitamin D status, and experimental data suggest that FGF23 may also suppress PTH, although most states of FGF23 excess are associated with increased PTH levels.