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Cited by 9Parathyroid Disorders and TreatmentsBone Metabolism and DiseasesElectrolyte and hormonal disorders

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Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation

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Radvanyi, Zsuzsa, Yoo, Eun Jin, Kandasamy, Palanivel, Salas-Bastos, Adrian, Monnerat, Sophie, Refardt, Julie, Christ-Crain, Mirjam, Hayashi, Himeka, Kondo, Yasuhiko, Jantsch, Jonathan, Rubio-Aliaga, Isabel, Sommer, Lukas, Wagner, Carsten A., Hediger, Matthias A., Kwon, Hyug Moo, Loffing, Johannes, Pathare, Ganesh·2024·Journal of Biological Chemistry
DOI 10.1016/j.jbc.2023.105480PMC PMC10770535

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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 (AVP), 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 vs. 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.

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  • The literature suggests that high sodium intake is associated with lower cFGF23 expression.

    “The literature suggests that high sodium intake is associated with lower cFGF23 expression [27, 29, 48, 62].”

    From Controlled dietary phosphate loading in healthy young men elevates plasma phosphate and FGF23 levels (2025) · cites this paper as [48]

    The Results section reports an inverse association between serum sodium and cFGF23, and the Abstract reports that elevated extracellular sodium suppressed FGF23 formation in cell lines. Neither establishes that high sodium intake is associated with lower cFGF23; the Abstract explicitly distinguishes dietary salt intake from plasma sodium levels. Page numbers are not available in our copy. (LLM, conf=0.85)

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Metadata

Authors
Radvanyi, Z., Yoo, E. J., Kandasamy, P., Salas-Bastos, A., Monnerat, S., Refardt, J., Christ-Crain, M., Hayashi, H., Kondo, Y., Jantsch, J., Rubio-Aliaga, I., Sommer, L., Wagner, C. A., Hediger, M. A., Kwon, H. M., Loffing, J., & Pathare, G.
Affiliations
  • Ulsan National Institute of Science and Technology (KR)
  • University of Bern (CH)
  • University of Basel (CH)
  • Teikyo University of Science (JP)
  • University of Cologne (DE)
  • University of Zurich (CH)
Corresponding author
Pathare, Ganesh
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2024-01
Volume
300
Issue
1
Pages
105480
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/j.jbc.2023.105480
PMC
PMC10770535
OpenAlex
W4388890296
Cited by
9
References
2
Citations by year
2026: 1 · 2025: 4 · 2024: 4
FWCI
1.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by)
Funders
  • University of Toledo
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (N-403-03-55)
  • Universität Zürich
Topics
  • Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Nephrology › Electrolyte and hormonal disorders
Keywords
fibroblast growth factor 23, extracellular sodium, hyponatremia, NFAT5, osteoblasts, UMR-106 cells, MC3T3-E1 cells, vasopressin, mannitol, urea, RNA-seq, CRISPR/Cas9 gene deletion, bone metabolism, chronic kidney disease, cardiovascular disease
MeSH terms
Fibroblast Growth Factor-23, Animals, Arginine Vasopressin, Cell Line, Fibroblast Growth Factors, Humans, Hyponatremia, Mice, Inbred C57BL, Osteoblasts, Sodium, Cell Line, Tumor, NFATC Transcription Factors, Mice, Rats, Renal Insufficiency, Chronic

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