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. 2022 Feb 24;23(5):2500. doi: 10.3390/ijms23052500

Figure 1.

Figure 1

FGF23 regulation and its interaction with the traditional paradigm on mineral homeostasis. FGF23 is mainly produced by osteoblasts and osteocytes, which is stimulated by calcitriol via the VDR signaling pathway and hyperphosphatemia via sensing of extracellular phosphate levels mediated by PiT2 (dominant pathway) and FGFR1c. In proximal tubular cells, FGF23 binding with the αKlotho/FGFR complex causes hypophosphatemia by inhibiting NaPi-2a and decreased calcitriol levels by suppressing the vitamin D activation process. Decreased calcitriol also reduces calcium and phosphate absorption from the GI tract. In parathyroid cells, PTH secretion is dominantly controlled by circulating calcium via CaSR, which overrides the inhibitory effect of FGF23. Increased PTH induces calcium resorption from bone and also causes hypophosphatemia by inhibiting NaPi-2a activity. Consequently, hypophosphatemia and decreased calcitriol levels will act as the negative feedback control of FGF23 production by diminishing VDR, PiT2 and FGFR1c signaling. This figure was generated with publication licensed by BioRender, Toronto, ON, Canada (Agreement number: VZ237SOI81, 19 November 2021). Abbreviations: CaSR, Calcium-sensing receptor; EP, Extracellular αKlotho; ERK1/2, Extracellular signal-regulated kinases; FL, Full-length αKlotho; FGF23, Fibroblast growth factor 23; FGFR, Fibroblast growth factor receptor; GALNT3, polypeptide N-acetyl.