The vitamin D₃ hormone, 1,25(OH)₂D₃, regulates fibroblast growth factor 23 (FGF23) production in human skin cells

The bone hormone fibroblast growth factor 23 (FGF23) regulates renal phosphate reabsorption and the enzymatic production of active vitamin D₃ [1,25(OH)₂D₃]. Therefore, FGF23 production in bone cells is closely regulated by 1,25(OH)₂D₃ acting via the vitamin D receptor (VDR). Skin cells can produce hydroxyvitamin D₃ metabolites from its precursor D₃ made through ultraviolet B light exposure. Interestingly, the expression of Fgf23 has been found in rodent skin, but its expression, regulation, and role in human skin are unclear. Therefore, we investigated whether hydroxyvitamin D₃ metabolites regulate FGF23 in human skin cells. Primary adult and neonatal epidermal keratinocytes (HEKn), melanocytes (HEMn), dermal fibroblasts (HDFn), as well as human melanoma cells, HaCaT, HaCaT VDR KO, and A431 epidermoid cells, were used to assess <i>FGF23</i> gene expression (quantitative reverse-transcription real-time PCR), cellular FGF23 protein (Western blot), or secreted FGF23 protein (ELISA) after treatment with hydroxyvitamin D₃ metabolites. HaCaT cells treated with recombinant FGF23 were used to explore its function in skin. Human skin cells can synthesize FGF23. Treatment with 1,25(OH)₂D₃ significantly increased <i>FGF23</i> mRNA levels in HaCaT and HDFn cells, and moderately in HEKn cells, mediated in part by the VDR. It also moderately enhanced mRNA levels of the FGF23-processing enzyme <i>GALNT3</i> and stimulated secretion of hormonally active FGF23 from HaCaT cells. Treatment of HaCaT cells with FGF23 increased mRNA levels of the cholesterol- and vitamin D-metabolizing enzymes, <i>CYP11A1</i> and <i>CYP27A1</i>. In conclusion, human skin cells express and secrete FGF23, which is regulated by 1,25(OH)₂D₃ acting in part by the VDR. FGF23 affects the expression of cutaneous sterol-metabolizing enzymes.<b>NEW & NOTEWORTHY</b> This study shows for the first time the expression and secretion of the FGF23 hormone by human skin cells. In addition, we identified the active vitamin D₃ hormone, 1,25(OH)₂D₃, to be a potent regulator of dermal FGF23 expression and protein secretion, partly involving the vitamin D receptor. Furthermore, we provide initial evidence demonstrating that FGF23 upregulates the gene expression of <i>CYP11A1</i> and <i>CYP27A1</i> in keratinocytes.