1,25-Dihydroxyvitamin D3 Regulation of Fibroblast Growth Factor-23 Expression in Bone Cells: Evidence for Primary and Secondary Mechanisms Modulated by Leptin and Interleukin-6

Saini, Rimpi K.; Kaneko, Ichiro; Jurutka, Peter W.; Forster, Ryan; Hsieh, Antony; Hsieh, Jui Cheng; Haussler, Mark R.; Whitfield, G. Kerr

doi:10.1007/s00223-012-9683-5

Cited by 81 publications

(70 citation statements)

References 51 publications

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“…We found a putative consensus Ets-1 site that overlaps an NFAT site adjacent to a CREB binding site at positions Ϫ182 and Ϫ165 bp in the mouse FGF-23 promoter (44). These sites were conserved in the human FGF-23 promoters.…”

Section: Fgfr-dependent Activation Of the Fgf-23 Promoter Through Plcmentioning

confidence: 79%

“…This approach would miss additional potential enhancers and transcriptional binding sites located at considerable distances from the transcription start site. Nevertheless, 1,25(OH) 2 D treatment of URM-106 osteoblasts resulted in enhancement in histone H4 acetylation in the proximal FGF-23 promoter between Ϫ57 and 259 bp (44), suggesting that the proximal promoter is important in FGF-23 gene transcription. Chip-seq investigations in human and mouse osteoblasts will be required to completely define the NFAT, ETS-1, CREB, and other potential binding sites that mediate FGFR1 regulation of FGF-23 gene transcription.…”

Section: Discussionmentioning

confidence: 96%

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Membrane and Integrative Nuclear Fibroblastic Growth Factor Receptor (FGFR) Regulation of FGF-23

Han

Xiao

Quarles

2015

Journal of Biological Chemistry

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Section: Fgfr-dependent Activation Of the Fgf-23 Promoter Through Plcmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 96%

Membrane and Integrative Nuclear Fibroblastic Growth Factor Receptor (FGFR) Regulation of FGF-23

Han

Xiao

Quarles

2015

Journal of Biological Chemistry

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“…LMW FGF2 acts through NFAT and ETS1 and the HMW FGF2 through cAMP and CREB binding to a Cre in the FGF23 promoter. 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).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

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

Hassan

Durlacher

Silver

et al. 2016

American Journal of Physiology-Renal Physiology

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Serum FGF23 is markedly elevated in chronic kidney disease and has been associated with poor long-term outcomes. FGF23 expression is increased by activation of the FGF receptor 1 (FGFR1) in rats with normal renal function and in vitro in bone-derived osteoblast-like cells. We studied the regulation of FGF23 by FGFR1 in vivo in acute and chronic uremia in mice and rats. Folic acid-induced acute kidney injury increased calvaria FGF23 mRNA and serum FGF23 and parathyroid hormone (PTH) levels at 6 h. The FGFR1 receptor inhibitor PD173074 prevented the folic acid-induced increase in both FGF23 mRNA and serum levels but had no effect on serum PTH levels. A more prolonged uremia due to an adenine high-phosphorus diet for 14 days resulted in high levels of FGF23 mRNA and serum FGF23 and PTH. PD173074 decreased serum FGF23 and mRNA levels with no effect on PTH in the adenine high phosphorus-induced uremic rats. Therefore, a derangement in FGF23 regulation starts early in the course of acute kidney injury, is in part independent of the increase in serum PTH, and involves activation of FGFR1. It is possible that FGFR1 in the osteocyte is activated by locally produced canonical FGFs, which are increased in uremia. This is the first demonstration that activation of FGFR1 is essential for the high levels of FGF23 in acute and chronic experimental uremia.FGF23; FGFR; acute kidney injury; uremia FGF23 IS PRODUCED BY OSTEOCYTES and osteoblasts, binds to its receptor, the fibroblast growth factor receptor 1 (FGFR1)-klotho heterodimer, in the kidney to cause a phosphaturia and decrease the synthesis of 1,25(OH) 2 vitamin D (25, 10). In addition, FGF23 acts on the FGFR1-klotho in the parathyroid to decrease parathyroid hormone (PTH) gene expression and parathyroid cell proliferation (2). In chronic kidney disease (CKD), there are extremely high levels of serum FGF23, which is one of the markers of the increased mortality in these patients (13). FGF23 also acts independently of klotho through FGFR1 and the calcineurin pathway in the heart and parathyroid (6,8,21). The synthesis and secretion of FGF23 by osteocytes are increased by a number of systemic factors (26). PTH acts through the nuclear orphan receptor nurr1, which binds to the FGF23 gene promoter to increase FGF23 transcription by PTH/PKA signaling (17). Conserved Nurr1 elements in the FGF23 proximal promoter and immediately preceding the start site for transcription mediate the increase in FGF23 transcription by PTH (20). 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). Calcium, phosphorus retention in the milieu of CKD, metabolic aci...

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“…1,25(OH) 2 D 3 enhances FGF23 expression via activation of the vitamin D receptor (VDR) (36,37). Parathyroid hormone (PTH) also stimulates FGF23 release (38)(39)(40).…”

mentioning

confidence: 99%

Enhanced FGF23 production in mice expressing PI3K‐insensitive GSK3 is normalized by β‐blocker treatment

Fajol¹,

Chen²,

Umbach³

et al. 2015

FASEB j.

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Glycogen synthase kinase (GSK)-3 is a ubiquitously expressed kinase inhibited by insulindependent Akt/PKB/SGK. Mice expressing Akt/PKB/ SGK-resistant GSK3a/GSK3b (gsk3 KI ) exhibit enhanced sympathetic nervous activity and phosphaturia with decreased bone density. Hormones participating in phosphate homeostasis include fibroblast growth factor (FGF)-23, a bone-derived hormone that inhibits 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ; calcitriol) formation and phosphate reabsorption in the kidney and counteracts vascular calcification and aging. FGF23 secretion is stimulated by the sympathetic nervous system. We studied the role of GSK3-controlled sympathetic activity in FGF23 production and phosphate metabolism. Serum FGF23, 1,25(OH) 2 D 3 , and urinary vanillylmandelic acid (VMA) were measured by ELISA, and serum and urinary phosphate and calcium were measured by photometry in gsk3 KI and gsk3 WT mice, before and after 1 wk of oral treatment with the b-blocker propranolol. Urinary VMA excretion, serum FGF23, and renal phosphate and calcium excretion were significantly higher, and serum 1,25(OH) 2 D 3 and phosphate concentrations were lower in gsk3 KI mice than in gsk3 WT mice. Propranolol treatment decreased serum FGF23 and loss of renal calcium and phosphate and increased serum phosphate concentration in gsk3 KI mice. We conclude that Akt/ PKB/SGK-sensitive GSK3 inhibition participates in the regulation of FGF23 release, 1,25(OH) 2 D 3 formation, and thus mineral metabolism, by controlling the activity of the sympathetic nervous system.-Fajol, A., Chen, H., Umbach, A. T., Quarles, L. D., Lang, F., Föller, M. Enhanced FGF23 production in mice expressing PI3K-insensitive GSK3 is normalized by b-blocker treatment. Insulin mainly regulates glucose homeostasis, but also affects renal phosphate handling (1, 2). Cellular insulin's effects are in large part mediated by activation of PI3K resulting in the stimulation of Akt/PKB and serum-and glucocorticoid-inducible kinase (SGK) isoforms (3, 4). Upon activation, Akt/PKB (5) and SGK (6, 7) isoforms can phosphorylate numerous cellular targets, including glycogen synthase kinase (GSK)-3, thereby rendering this kinase inactive. Loss of Akt2 or of SGK3 activity in mouse models results in decreased renal phosphate reabsorption and, hence, phosphate loss (8, 9). Moreover, transgenic mice expressing Akt/PKB/SGK-resistant GSK3a/b [gsk-3 knockin (gsk-3 KI )] have hypophosphatemia, phosphaturia, and decreased bone density, illustrating the significance of PI3K signaling for renal phosphate handling (10). A direct inhibitory effect of GSK3 on renal sodium-dependent phosphate transporter IIa (NaPiIIa) (10) is likely to contribute to the phosphaturia of gsk-3 KI mice, but may not fully explain it. Gsk-3 KI mice also have hypertension and a faster heart rate caused by enhanced sympathetic activity (11).Fibroblast growth factor (FGF)-23 is a bone-derived hormone that controls phosphate and calcium metabolism (12-14). Its main target is the kidney, where FGF23 inhibits tubular p...

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1,25-Dihydroxyvitamin D3 Regulation of Fibroblast Growth Factor-23 Expression in Bone Cells: Evidence for Primary and Secondary Mechanisms Modulated by Leptin and Interleukin-6

Cited by 81 publications

References 51 publications

Membrane and Integrative Nuclear Fibroblastic Growth Factor Receptor (FGFR) Regulation of FGF-23

Membrane and Integrative Nuclear Fibroblastic Growth Factor Receptor (FGFR) Regulation of FGF-23

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

Enhanced FGF23 production in mice expressing PI3K‐insensitive GSK3 is normalized by β‐blocker treatment

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