Regulation of serum 1,25(OH)₂Vitamin D₃levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4

Abstract

Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in the pathogenesis of several hypophosphatemic disorders. FGF23 causes hypophosphatemia by decreasing the expression of sodium phosphate cotransporters (NaPi-2a and NaPi-2c) and decreasing serum 1,25(OH)2Vitamin D3 levels. We previously showed that FGFR1 is the predominant receptor for the hypophosphatemic actions of FGF23 by decreasing renal NaPi-2a and 2c expression while the receptors regulating 1,25(OH)2Vitamin D3 levels remained elusive. FIBROBLAST GROWTH FACTOR 23 (FGF23) is a phosphaturic hormone that has been implicated in several inherited and acquired hypophosphatemic disorders (15). FGF23 increases urinary phosphate excretion by decreasing renal brush-border expression of the sodium phosphate cotransporters 2a and 2c (NaPi-2a and NaPi-2c) (14, 42). In addition, FGF23 decreases the expression of 25(OH)Vitamin D-1␣-hydroxylase (CYP27B1) and increases the expression 24-hydroxylase (CYP24) resulting in low-serum 1,25(OH) 2 Vitamin D 3 levels (37, 42). The inherited hypophosphatemic disorders where FGF23 levels are increased include X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, and autosomal recessive hypophosphatemic rickets (12,14,21,24,31,36,50). The increased FGF23 levels in these disorders result in severe hypophosphatemia, rickets/osteomalacia, bone pain, fractures, and growth failure in children. Serum FGF23 levels are also elevated in tumor-induced osteomalacia (8, 9).The FGF family of ligands bind to FGF receptors (FGFRs) to mediate their actions (10,17,23,34). Four FGFRs (FGFR1-4) are encoded by four genes and alternative splicing (b and c isoforms of FGFR1-3) results in tissue and ligand binding specificity (33,35). The proximal tubule, the site of most renal phosphate reabsorption (4, 46) and 25(OH)Vitamin D-1␣-hydroxylase activity (7, 13), has FGFR1, 3, and 4, but it does not express FGFR2 (14).We previously utilized FGFR-null mice with the goal of determining which receptor was responsible for the FGF23-mediated decrease in renal phosphate transport and vitamin D production. In these studies, FGF23 was administered to conditional FGFR1Ϫ/Ϫ , and FGFR4 Ϫ/Ϫ mice. FGFR1 was found to be the predominant receptor mediating the hypophosphatemic actions of FGF23 by decreasing brushborder membrane (BBM) NaPi-2a and NaPi-2c expression with FGFR4 playing an additional but relatively minor role (14). Liu et al. (29) also found that deletion of either FGFR3 or FGFR4 in a mouse model of X-linked hypophosphatemic rickets (Hyp mouse) did not correct the disturbances in phosphate homeostasis. Intriguingly, in the conditional FGFR1 Ϫ/Ϫ mice, as well as FGFR3 Ϫ/Ϫ and FGFR4 Ϫ/Ϫ mice, 1,25(OH) 2 Vitamin D 3 levels decreased comparably after administration of FGF23 (14). This implies that FGF23 regulates proximal tubular 1,25(OH) 2 Vitamin D 3 biosynthesis using a different receptor than for the inhibition of phosphate transport in the proximal tubule. 1,25(OH) 2 Vitamin D 3 is primarily synthesized in the pr...

Molecular Pathways: Fibroblast Growth Factor Signaling: A New Therapeutic Opportunity in Cancer

“…The FGFR pathway is involved in normal phosphate and vitamin D homeostasis, and preclinical development of FGFR inhibitors has been complicated by hyperphosphatemia-mediated tissue calcification, owing to blockade of FGF23 release from bone and of the FGF23 signal in kidney (47). FGF23 binds FGFR4 and the IIIc isoforms of FGFR1 and FGFR3 (2,48), but uncertainty remains about the relative contribution of individual FGFR subtypes to hyperphosphatemia (49)(50)(51)(52). In preclinical models, FGFR inhibition results in dynamic modulation of circulating FGF23 levels, with suppressed levels observed during periods of drug exposure (attributable to direct inhibition of FGF23 release from bone) and elevated levels upon drug withdrawal (driven by increased plasma phosphate and vitamin D levels acting on bone to stimulate FGF23 production; ref.…”

RECENT RESEARCH ON THE GROWTH PLATE: Advances in fibroblast growth factor signaling in growth plate development and disorders

“…Krejci . Further studies revealed that Fgfr3/Fgfr4 double-null mice have lower serum phosphorus levels and elevated FGF23 and 1,25(OH) 2-vitamin D 3 levels compared with WT mice (Gattineni et al 2011). The supraphysiological levels FGF23 and 1,25(OH) 2-vitamin D 3 may be responsible for the growth retardation of Fgfr3/Fgfr4 double-null mice (Larsson et al 2004, Kawai et al 2013, Bach et al 2014.…”

Functional heterogeneity of osteocytes in FGF23 production: the possible involvement of DMP1 as a direct negative regulator

“…19,20 FGF23 reduces the 1,25-dihydroxyvitamin level by inhibiting the renal 1-a-hydroxylase expression and promoting the 24-hydroxylase expression, thereby downregulating the amount of phosphate absorption from the gut and resorption from the bone. 21,22 Mutual regulation of FGF23 and parathyroid hormone has been reported in rodent models 23,24 and identified in clinical cases of hypophosphatemic rickets and chronic kidney disease. 25 In addition to these systemic and hormonal patterns of regulation, the FGF23 expression appears to be regulated locally by FGF23-producing cells and osteocytes through molecules such as dentin matrix protein-1 (DMP1) 26,27 and the phosphate-regulating gene with homology to endopeptidases on X chromosome (PHEX), 28 both of which are highly expressed in osteocytes.…”