Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation.
Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that has recently received much attention due to its association with the progression of chronic kidney disease, cardiovascular disease, and associated mortality. Extracellular sodium ion concentration ([Na+]) plays a significant role in bone metabolism. Both hyponatremia (low serum [Na+]) and hypernatremia (high serum [Na+]) have been shown to affect bone remodeling. However, nothing is known about the impact of [Na+] on FGF23 production. Here, we show that elevated [Na+] (by +20 mM) suppressed FGF23 formation, whereas low [Na+] (by -20 mM) led to an increase in FGF23 synthesis in the osteoblast-like cell line UMR-106. Similar bidirectional changes in FGF23 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. On the other hand, arginine vasopressin (AVP), which is often responsible for hyponatremia, did not affect FGF23 production. Next, comprehensive and unbiased RNA-seq analysis of UMR-106 cells exposed to low vs. high [Na+] 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 findings, in a pilot study, we found that human hyponatremic patients have higher FGF23 levels. Our results suggest that [Na+] is a critical regulator of FGF23 synthesis.