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Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation.

ABSTRACT: The bone-derived hormone fibroblast growth factor-23 (FGF23) has recently received much attention due to its association with chronic kidney disease and cardiovascular disease progression. Extracellular sodium concentration ([Na⁺]) plays a significant role in bone metabolism. Hyponatremia (lower serum [Na⁺]) has recently been shown to be independently associated with FGF23 levels in patients with chronic systolic heart failure. However, nothing is known about the direct impact of [Na⁺] on FGF23 production. Here, we show that an elevated [Na⁺] (+20 mM) suppressed FGF23 formation, whereas low [Na⁺] (-20 mM) increased FGF23 synthesis in the osteoblast-like cell lines UMR-106 and MC3T3-E1. Similar bidirectional changes in FGF23 abundance were observed when osmolality was altered by mannitol but not by urea, suggesting a role of tonicity in FGF23 formation. Moreover, these changes in FGF23 were inversely proportional to the expression of NFAT5 (nuclear factor of activated T cells-5), a transcription factor responsible for tonicity-mediated cellular adaptations. Furthermore, arginine vasopressin, which is often responsible for hyponatremia, did not affect FGF23 production. Next, we performed a comprehensive and unbiased RNA-seq analysis of UMR-106 cells exposed to low versus high [Na⁺], which revealed several novel genes involved in cellular adaptation to altered tonicity. Additional analysis of cells with Crisp-Cas9-mediated NFAT5 deletion indicated that NFAT5 controls numerous genes associated with FGF23 synthesis, thereby confirming its role in [Na⁺]-mediated FGF23 regulation. In line with these in vitro observations, we found that hyponatremia patients have higher FGF23 levels. Our results suggest that [Na⁺] is a critical regulator of FGF23 synthesis.

SUBMITTER: Radvanyi Z

PROVIDER: S-EPMC10770535 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation.

Radvanyi Zsuzsa Z Yoo Eun Jin EJ Kandasamy Palanivel P Salas-Bastos Adrian A Monnerat Sophie S Refardt Julie J Christ-Crain Mirjam M Hayashi Himeka H Kondo Yasuhiko Y Jantsch Jonathan J Rubio-Aliaga Isabel I Sommer Lukas L Wagner Carsten A CA Hediger Matthias A MA Kwon Hyug Moo HM Loffing Johannes J Pathare Ganesh G

The Journal of biological chemistry 20231121 1

The bone-derived hormone fibroblast growth factor-23 (FGF23) has recently received much attention due to its association with chronic kidney disease and cardiovascular disease progression. Extracellular sodium concentration ([Na<sup>+</sup>]) plays a significant role in bone metabolism. Hyponatremia (lower serum [Na<sup>+</sup>]) has recently been shown to be independently associated with FGF23 levels in patients with chronic systolic heart failure. However, nothing is known about the direct imp ...[more]

PMID: 37992803

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Project description:Fibroblast growth factor 23 (FGF23) is a hormone mainly secreted by bone cells. Its most prominent effects are the regulation of renal phosphate reabsorption and calcitriol (active vitamin D, 1,25(OH)2D3) formation, effects dependent on its co-receptor αKlotho. Besides these actions, further paracrine and endocrine effects exist. The production of FGF23 is regulated by 1,25(OH)2D3, parathyroid hormone, dietary phosphate intake, iron status, as well as inflammation. Glucocorticoids are hormones with anti-inflammatory properties and are, therefore, widely used for acute and chronic inflammatory diseases, autoimmune disorders, and malignancies. The present study explored whether glucocorticoids influence the production of FGF23 in vitro as well as in mice. Fgf23 transcription was analyzed by semi-quantitative real-time PCR. Serum concentrations of FGF23 and 1,25(OH)2D3 were measured by ELISA. Urinary phosphate and Ca2+ excretion were determined in metabolic cages. As a result, in UMR106 rat osteoblast-like cells and in MC3T3-E1 cells, both, dexamethasone and prednisolone, downregulated Fgf23 transcription and FGF23 protein synthesis. Dexamethasone increased Dmp1 and Phex (encoding FGF23-regulating genes) as well as Nfkbia (encoding NFκB inhibitor IκBα) transcription in UMR106 cells. In mice, a single injection of dexamethasone or prednisolone was followed by a significant decrease of serum C-terminal and intact FGF23 concentration and bone Fgf23 mRNA expression within 12 h. These effects were paralleled by increased renal phosphate excretion and enhanced 1,25(OH)2D3 formation. We conclude that a single glucocorticoid treatment strongly downregulates the FGF23 plasma concentration. KEY MESSAGES: Glucocorticoids dexamethasone and prednisolone suppress the formation of bone-derived hormone fibroblast growth factor 23 (FGF23) in vitro. The effect is accompanied by an upregulation of Dmp1, Phex, and IκBα, negative regulators of FGF23, in UMR106 osteoblast-like cells. Glucocorticoid receptor antagonist RU-486 attenuates the effect of dexamethasone on FGF23, Dmp1, and Phex. In mice, a single glucocorticoid dose suppresses FGF23 and enhances 1,25(OH)2D3 (active vitamin D).

Project description:Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by ectopic production of fibroblast growth factor 23 (FGF23) by phosphaturic mesenchymal tumors (PMTs). Acting on renal tubule cells, excess FGF23 decreases phosphate reabsorption and 1,25-dihydroxy-vitamin D (1,25D) production, leading to hypophosphatemia, impaired bone mineralization, pain, and fractures. Fibronectin 1-fibroblast growth factor receptor 1 (FN1-FGFR1) gene fusions have been identified as possible drivers in up to 40% of resected PMTs. Based on the presumptive role of FGFR1 signaling by chimeric FN1-FGFR1 proteins, the effectiveness of infigratinib, a FGFR1-3 tyrosine kinase inhibitor, was studied in an open-label, single-center, phase 2 trial. The primary endpoint was persistent normalization of blood phosphate and FGF23 after discontinuation. Four adults with TIO (two nonlocalized, two nonresectable PMTs) were treated with daily infigratinib for up to 24 weeks. All patients had a favorable biochemical response that included reduction in intact FGF23, and normalization of blood phosphate and 1,25D. However, these effects disappeared after drug discontinuation with biochemistries returning to baseline; no patients entered biochemical remission. In the two patients with identifiable tumors, 68Gallium (68Ga)-DOTATATE and 18Fluoride (18F)-Fluorodeoxyglucose (FDG) PET/CT scans showed a decrease in PMT activity without change in tumor size. Patients experienced mild to moderate, treatment-related, dose-limiting adverse events (AEs), but no serious AEs. Three patients had dose interruptions due to AEs; one patient continued on a low dose for the entire 24 weeks and one patient stopped therapy at 17 weeks due to an AE. The study closed early due to a failure to meet the primary endpoint and a higher-than-expected incidence of ocular AEs. Infigratinib treatment lowered FGF23, increased blood phosphate, and suppressed PMT activity, confirming the role of FGFR signaling in PMT pathogenesis. However, treatment-related AEs at efficacy doses and disease persistence on discontinuation support restricting the use of infigratinib to patients with life-limiting metastatic PMTs. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Dataset Information

Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation.

Publications

Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation.

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