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. 2020 Aug 28;11:592. doi: 10.3389/fendo.2020.00592

Figure 1.

Figure 1

FGF23 regulation in osteocytes. In osteocytes, FGF23 is positively regulated by different factors and pathways (shown in green). In presence of high phosphate, the receptor FGFR1 may sense this condition and the adaptor FRS2α is phosphorylated thus activating FGFR1 and the MEK/pERK/EGR1 pathway leading to FGF23 transcription. It is also possible that the transporter PiT2 senses phosphate increases in osteocyte and responds by inducing FGF23. The activation of FGFR1 by other FGFs such as FGF2 may induce Pi3K/AKT/pERK/EGR1 leading to FGF23 upregulation. The activation of PTH1R by PTH induces cAMP/PKA and the transcription factor NURR1 leading to FGF23 induction. Inflammatory conditions are potent FGF23 inducers; lipopolysaccharide (LPS) may bind to osteocyte toll like receptor 4 (TLR4) and induce MyD88/IRAK/TRAF6/NF-κB to trigger FGF23 transcription (or may act through anemia/hypoxia). The binding of IL-6 to IL-6R in osteocytes may induce JAK/STAT3 and subsequent FGF23 expression. The cytokines IL-1β and TNF-α can induce NF-κB in osteocytes leading to FGF23 transcription. In the condition of iron deficiency, HIF protein is stabilized, an important mechanism involved in FGF23 upregulation. The active form of vitamin D (1,25-dihydroxyvitamin D; 1,25D), which results from the conversion of 25-hydroxyvitamin D (25D) inside or outside the osteocyte, could promote the formation of the complex 1,25D-VDR-RXR which binds the vitamin D receptor element (VDRE, not shown here) and induces FGF23 transcription. The signaling through the TGF-β-Activin Receptors ALK4/5/7 promotes calcium entry in cell through Orai1 and this process activates calcineurin and NFAT and their binding, which induces FGF23. Lithium-induced increased intracellular calcium could also increase FGF23 in osteocytes through calcineurin and NFAT activity. An activation of a yet unknown GPRC could trigger FGF23 transcription through XLαs or Gq/11α and inositol 1,4,5-trisphosphate (IP3) which may activate PKC and stimulate the MAPK pathway. FGF23 can be negatively regulated by other elements and pathways (shown in red). For instance, insulin can bind to IGFR1 and induce PI3K/AKT/FOXO1 pathway which represses FGF23. Phex and Dmp1 activities in osteocytes may control FGFR1/PI3KR1/GRB and cell differentiation to restrain FGF23 production. Dmp1 activity may also neutralize the FAK/MAPK pathway restricting FGF23 expression.