Abstract
Endocrine and paracrine fibroblast growth factor 23 (FGF23) is a protein predominantly produced by bone cells with strong impact on phosphate and vitamin D metabolism by targeting the kidney. Plasma FGF23 concentration early rises in kidney and cardiovascular diseases correlating with progression and outcome. Lactic acid is generated in anaerobic glycolysis. Lactic acidosis is the consequence of various physiological and pathological conditions and may be fatal. Since FGF23 production is stimulated by inflammation and lactic acid induces pro-inflammatory signaling, we investigated whether and how lactic acid influences FGF23. Experiments were performed in UMR106 osteoblast-like cells, Fgf23 mRNA levels estimated from quantitative real-time polymerase chain reaction, and FGF23 protein determined by enzyme-linked immunosorbent assay. Lactic acid dose-dependently induced Fgf23 gene expression and up-regulated FGF23 synthesis. Also, Na+-lactate as well as formic acid and acetic acid up-regulated Fgf23. The lactic acid effect was significantly attenuated by nuclear factor kappa-light-chain enhancer of activated B-cells (NFκB) inhibitors wogonin and withaferin A. Lactic acid induces FGF23 production, an effect at least in part mediated by NFκB. Lactic acidosis may, therefore, be paralleled by a surge in plasma FGF23.
Highlights
Bone cells are the main source of fibroblast growth factor 23 (FGF23), a proteohormone with additional paracrine effects [1,2,3,4]
The aforementioned endocrine effects of FGF23 are dependent on a membrane receptor which assembles with transmembrane protein αKlotho [13,14,15]
In a first series of experiments, these cells were treated with different concentrations of lactic acid for 24 h, and subsequently Fgf23 gene expression was determined by qRT-PCR
Summary
Bone cells are the main source of fibroblast growth factor 23 (FGF23), a proteohormone with additional paracrine effects [1,2,3,4]. It regulates vitamin D and phosphate homeostasis in the kidney by down-regulating CYP27B1, the key enzyme for activation of vitamin D, and NaPiIIa, the major Na+-dependent phosphate transporter [5,6,7,8]. FGF23, 1,25(OH)2D3, and PTH are part of a complex hormone circuit influencing each other and controlling phosphate as well as Ca2+ homeostasis [5]. The aforementioned endocrine effects of FGF23 are dependent on a membrane receptor which assembles with transmembrane protein αKlotho [13,14,15]. Apart from being the co-receptor for FGF23, αKlotho has become known as a powerful anti-aging factor: Transmembrane αKlotho can release a fragment called soluble Klotho (sKL) with additional endocrine effects including anti-cancer activity [16,17,18,19].
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