Physiological Actions of Fibroblast Growth Factor-23

Abstract

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone suppressing phosphate reabsorption and vitamin D hormone synthesis in the kidney. At physiological concentrations of the hormone, the endocrine actions of FGF23 in the kidney are αKlotho-dependent, because high-affinity binding of FGF23 to FGF receptors requires the presence of the co-receptor αKlotho on target cells. It is well established that excessive concentrations of intact FGF23 in the blood lead to phosphate wasting in patients with normal kidney function. Based on the importance of diseases associated with gain of FGF23 function such as phosphate-wasting diseases and chronic kidney disease, a large body of literature has focused on the pathophysiological consequences of FGF23 excess. Less emphasis has been put on the role of FGF23 in normal physiology. Nevertheless, during recent years, lessons we have learned from loss-of-function models have shown that besides the paramount physiological roles of FGF23 in the control of 1α-hydroxylase expression and of apical membrane expression of sodium-phosphate co-transporters in proximal renal tubules, FGF23 also is an important stimulator of calcium and sodium reabsorption in distal renal tubules. In addition, there is an emerging role of FGF23 as an auto-/paracrine regulator of alkaline phosphatase expression and mineralization in bone. In contrast to the renal actions of FGF23, the FGF23-mediated suppression of alkaline phosphatase in bone is αKlotho-independent. Moreover, FGF23 may be a physiological suppressor of differentiation of hematopoietic stem cells into the erythroid lineage in the bone microenvironment. At present, there is little evidence for a physiological role of FGF23 in organs other than kidney and bone. The purpose of this mini-review is to highlight the current knowledge about the complex physiological functions of FGF23.

Importance of Dietary Phosphorus for Bone Metabolism and Healthy Aging

“…Thereby, high dietary phosphorus is associated with increased risk for bone fractures, as shown in a study of 2420 Brazilian individuals in whom every 100 mg of dietary phosphorus intake increased the risk of fracture by 9% [ 241 ]. Recent insights suggest that FGF23 (whose levels are determined by P i concentrations) may impair bone matrix mineralization independently of calcium by transcriptionally suppressing TNAP (although this effect also suppresses OPN) [ 242 , 243 ]. High phosphate containing soft drinks may finally affect dental mineralization, as discussed later in this review.…”

Protective Role of Vitamin D in Renal Tubulopathies

“…Furthermore, FGF23 reduces renal production of 1,25(OH)2D3 [85] and PTH secretion [96]. FGF23 suppresses the expression of 1α-hydroxylase enzyme in the kidney and induces the synthesis of 25-hydroxyvitamin D24-hydroxylase enzyme; this mechanism leads to a reduced conversion of 25(OH)D into 1,25(OH)2D and increased catabolism of 25(OH)D and 1,25(OH)2D3 into inactive carboxylic acids [97,98] (Figure 2). The Paracalcitol and ENdothelial fuNction in chronic kidneY disease (PENNY) study [99] showed that paricalcitol reduced serum PTH (−75.1 pg/mL, 95% CI −90.4 to −59.8; p < 0.001) and its action is linked to increased FGF23 levels ( + 107 pg/mL, 95% CI 44 to 170; p = 0.001).…”

Endothelin receptor B controls the production of fibroblast growth factor 23

“…Fibroblast growth factor 23 (FGF23) is a protein with endocrine and paracrine effects . It is mainly synthesized by bone cells, but also other cells including immune cells and cardiomyocytes produce it .…”