Neither absence nor excess of FGF23 disturbs fetal phosphate metabolism in mice until after birth

Ma, Yue (2020) Neither absence nor excess of FGF23 disturbs fetal phosphate metabolism in mice until after birth. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Fibroblast growth factor 23 (FGF23) plays an important role in maintaining phosphate homeostasis in adults largely though actions on the kidneys to excrete phosphate and reduce calcitriol. However, whether FGF23 is essential in maintaining phosphate homeostasis in fetuses had been largely unknown prior to my Ph.D. project, which hypothesized that FGF23 was important in regulating not only fetal serum phosphate and skeletal development, but also placental phosphate transport. However, studies in Phex null fetuses showed that excess FGF23 did not disturb any phosphate parameter or placental phosphate transport. Although the expression of Cyp24a1 was increased in the null placenta and kidneys and the expression of Klotho was decreased in the null kidneys, these changes did not disturb any physiological parameter related to phosphate, which suggests that FGF23 is not important in fetal phosphate regulation. Previous studies in Fgf23 null fetuses showed FGF23 absence did not alter fetal phosphate parameters, placental phosphate transport or skeletal development. These results led to my hypothesis that other FGF members might compensate for FGF23 loss by acting on the FGFR/Klotho receptor complex. However, studies in Klotho null fetuses showed that serum FGF23 was normal and that they had a similar phenotype as Fgf23 nulls – which rejected my hypothesis. Previous studies showed that Pth null fetuses developed hyperphosphatemia. I then studied Pth/Fgf23 double knockout (DKO) fetuses to determine if absence of FGF23 would potentiate hyperphosphatemia in Pth nulls. The results showed that DKO had the same elevation in serum phosphate as Pth nulls and there were no skeletal mineral content changes between the two genotypes either. I finally examined the postnatal time course of phosphate metabolism in neonatal Fgf23 nulls, Klotho nulls, and Phex nulls, respectively. The results showed Fgf23 nulls and Klotho nulls were normal at birth, but developed hyperphosphatemia, increased renal gene expression of NaPi2a and NaPi2c, and increased renal phosphate reabsorption between 5 and 7 days later. In contrast, excess FGF23 exerted effects in Phex nulls within 12 hours after birth, with the development of hypophosphatemia, reduced renal expression of NaPi2a and NaPi2c, and decreased renal phosphate reabsorption. In conclusion, my Ph.D. project suggests FGF23 is not an important regulator of fetal phosphate metabolism.

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