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Endocrine Abstracts (2015) 37 S6.2 | DOI: 10.1530/endoabs.37.S6.2

University of Veterinary Medicine Vienna, Vienna, Austria.


Fibroblast growth factor-23 (FGF23) FGF23 is a bone-derived hormone which down-regulates renal proximal tubular phosphate reuptake and 1α-hydroxylase expression, the key enzyme for production of the vitamin D hormone, 1α, 25-dihydroxyvitamin D3 (1.25(OH)2D). The molecular mechanism of the phosphaturic action of FGF23 has recently been elucidated. FGF23 directly downregulates membrane expression of the sodium-phosphate cotransporter NaPi-2a in proximal tubular epithelium by serine phosphorylation of the scaffolding protein Na+/H+ exchange regulatory cofactor (NHERF)-1 through FGF receptor-αKlotho complex-mediated activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and serum/glucocorticoid-regulated kinase-1 (SGK1). However, FGF23 not only targets renal proximal tubular cells, but also has distinct effects on the distal nephron, in bone, and possibly in the heart and in blood vessels. In renal distal tubules, FGF23 stimulates apical membrane abundance of TRPV5 and renal calcium reabsorption in a αKlotho dependent manner through a signaling cascade involving ERK1/2, SGK1, and with-no-lysine kinase-4 (WNK4). Because activation of WNK4 not only upregulates membrane transport of TRPV5 but also of the sodium-chloride co-transporter NCC, FGF23 also increases sodium reabsorption in distal renal tubules. Recent experimental evidence suggests that the calcium- and sodium-conserving function of FGF23 may be of pivotal importance in the pathophysiology of chronic kidney disease. In bone, we identified FGF23 as a strong transcriptional suppressor of alkaline phosphatase in osteoblastic cells, acting through FGF receptor-3 in a Klotho independent manner. Hence, FGF23 secreted from osteocytes may form an autocrine/paracrine feedback loop for the local fine-tuning of bone mineralization. Taken together, there is emerging evidence that FGF23 is not only a phosphaturic and vitamin D-regulating hormone, but rather a pleiotropic hormone with additional direct effects on calcium homeostasis, sodium homeostasis, blood pressure regulation, and bone mineralization.

Disclosure: Austrian Science Fund FWF P 24186-B21.

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