Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation

• Published in: The Journal of biological chemistry 2024-01, Vol.300 (1), p.105480-105480, Article 105480
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Arginine Vasopressin - metabolism; Cell Line; Cell Line, Tumor; Fibroblast Growth Factor-23 - genetics; Fibroblast Growth Factor-23 - metabolism; Humans; Hyponatremia - physiopathology; Mice; Mice, Inbred C57BL; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; Osteoblasts - cytology; Osteoblasts - drug effects; Osteoblasts - metabolism; Rats; Renal Insufficiency, Chronic - physiopathology; Sodium - metabolism; Sodium - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2023.105480

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.