FGF23 gene regulation by 1,25-dihydroxyvitamin D: opposing effects in adipocytes and osteocytes

Abstract

In a closed endocrine loop, 1,25-dihydroxyvitamin D3 (1,25D) induces the expression of fibroblast growth factor-23 (FGF23) in bone, with the phosphaturic peptide in turn acting at kidney to feedback repress CYP27B1 and induce CYP24A1 to limit the levels of 1,25D. In 3T3-L1 differentiated adipocytes, 1,25D represses FGF23 and leptin expression, while not affecting leptin receptor transcription, but inducing C/EBP. Conversely, in UMR-106 osteoblast-like cells, FGF23 mRNA concentrations are upregulated by 1,25D, an effect that is blunted by lysophosphatidic acid, a cell-surface acting ligand. Progressive truncation of the mouse FGF23 proximal promoter linked in luciferase reporter constructs reveals a 1,25D-responsive region between −400 and −200 bp. A 0.6 kb fragment of the mouse FGF23 promoter, linked in a reporter construct, responds to 1,25D with a 4-fold enhancement of transcription in transfected K562 cells. Mutation of either an ETS1 site at −346 bp, or an adjacent candidate VDR/Nurr1-element, in the 0.6 kb reporter construct reduces the transcriptional activity elicited by 1,25D to a level that is not significantly different from a minimal promoter. This composite ETS1-VDR/Nurr1 cis-element may function as a switch between induction (osteocytes) and repression (adipocytes) of FGF23, depending on the cellular setting of transcription factors. Moreover, experiments demonstrate that a 1kb mouse FGF23 promoter-reporter construct, transfected into MC3T3 osteoblast-like cells, responds to high calcium challenge with a statistically significant 1.7–2.0-fold enhancement of transcription. Thus, the FGF23 proximal promoter harbors cis-elements that drive responsiveness to 1,25D and calcium, agents that induce FGF23 to curtail the pathologic consequences of their excess.

Multiple faces of fibroblast growth factor-23

“…Interestingly, PTH stimulates Nurr1 expression in osteoblasts prior to FGF-23 elevations and Nurr1 is essential for PTH regulation of FGF-23 gene transcription in UMR-106 osteoblasts [59–61]. VDR is known to activate Nurr1 in T-cells [62], raising the possibility that Nurr1 might also mediate the responses to 1,25(OH) 2 D to regulate FGF-23 gene transcription [63]. …”

FGF23-Klotho signaling axis in the kidney

“…There is good evidence that FGF23 is secreted by both osteocytes and osteoblasts in bone [7,8]. Bony FGF23 secretion is stimulated by 1,25(OH) 2 D and by increased extracellular phosphate, thus forming a feedback loop between kidney and bone [5,9,10].…”

The fibroblast growth factor receptor mediates the increased FGF23 expression in acute and chronic uremia

“…1,25(OH) 2 vitamin D upregulates ETS1, which cooperates with VDR (7,24). An ETS1-VDRE/Nurr1 composite conserved element has recently been defined in the FGF23 proximal promoter (14). The proximity of these elements may allow interactions among the FGFR pathway through ETS1 and Cre, PPR, and PTH action through Nurr1 and VDR through the VDRE/ETS1.…”

“…FGF23 expression is also enhanced by 1,25(OH) 2 vitamin D, which binds to a vitamin D-response element (VDRE) in the FGF23 promoter (15). One of the Nurr1 elements at the Ϫ200-to Ϫ399-bp region of the mouse FGF23 promoter is part of a VDRE in the FGF23 promoter (14). This vitamin D receptor (VDR)/Nurr1-element mediates the effect of 1,25(OH) 2 vitamin D and is a cisregulatory module anchored by adjacent ETS1, a transcription factor that cooperates with VDR (4,24), and VDRE/Nurr1 sites (14).…”

“…One of the Nurr1 elements at the Ϫ200-to Ϫ399-bp region of the mouse FGF23 promoter is part of a VDRE in the FGF23 promoter (14). This vitamin D receptor (VDR)/Nurr1-element mediates the effect of 1,25(OH) 2 vitamin D and is a cisregulatory module anchored by adjacent ETS1, a transcription factor that cooperates with VDR (4,24), and VDRE/Nurr1 sites (14). Calcium, phosphorus retention in the milieu of CKD, metabolic acidosis, estrogens, leptin, and cleaved klotho have all been shown to increase serum FGF23 levels (16,23,27).…”