Neither Absence Nor Excess of FGF23 Disturbs Murine Fetal-Placental Phosphorus Homeostasis or Prenatal Skeletal Development and Mineralization

Abstract

Fibroblast growth factor-23 (FGF23) controls serum phosphorus largely through actions on the kidneys to excrete phosphorus and reduce calcitriol. Although these actions are well established in adults and children, the role that FGF23 plays in regulating fetal phosphorus metabolism has not been previously studied. We used several mouse models to study the effect of endogenous deficiency or excess of FGF23 on fetal phosphorus metabolism. We found that intact FGF23 does not cross the placenta from mother to fetus, but wild-type fetuses normally have intact FGF23 levels that approximately equal the maternal level. Deletion of Fgf23 or 7.8-fold higher serum FGF23 levels did not disturb any parameter of fetal mineral homeostasis, including serum and amniotic fluid phosphorus, skeletal morphology, skeletal mineral content, and placental phosphorus transport. Placentas and fetal kidneys abundantly express FGF23 target genes. Cyp24a1 was significantly reduced in Fgf23 null kidneys and was significantly increased in Phex null placentas and fetal kidneys. Phex null kidneys also showed reduced expression of Klotho. However, these changes in gene expression did not disturb any physiological parameter related to phosphorus. A 50% reduction in FGF23 also failed to affect renal phosphorus excretion into amniotic fluid when either PTH or the vitamin D receptor were absent. In conclusion, FGF23 is not an important regulator of fetal phosphorous metabolism. The active delivery of phosphorus across the placenta does not require FGF23, and that process overrides any effects that absence or excess of FGF23 might otherwise have on phosphate handling by the fetal kidneys.

Bone Development and Mineral Homeostasis in the Fetus and Neonate: Roles of the Calciotropic and Phosphotropic Hormones

“…The concentration of intact FGF23 in fetal blood from WT fetuses was equal to the simultaneous maternal level in mice from the outbred Black Swiss strain for several mouse models (395), whereas the level was about half the maternal value in WT fetuses from the inbred C57BL/6 strain (194,395). The maternal value in turn was approximately double the nonpregnant level as revealed through longitudinal studies in both strains of mice (194).…”

“…It is typically 0.5-1.0 mM higher in the fetus than in the mother, as observed in rats (211,213,315,346), mice (623), lambs (377,403,435), pigs (98,353), calves (201), and foals (201). Fetuses maintained normal phosphorus levels despite hypophosphatemia in pregnant rats and mice (207,395). Conversely, hyperphosphatemia in pregnant rats and sheep caused fetal hyperphosphatemia (41,199,206,208).…”

“…Casr null Calcium sensing receptor (CaSR) (257,338) Casr Chon, Pre, Ob, Oc, Para null Calcium sensing receptor, conditionally deleted from chondrocytes, preosteoblasts, osteoblasts, osteocytes, and parathyroids, respectively (109,169,549) Ctcgrp null Calcitonin and calcitonin gene-related peptide-␣ (119,260,430,744) Ctr null Calcitonin receptor (134,361) Cyp27b1 null 1␣-Hydroxylase/Cyp27b1 (cytochrome P-450, family 27, subfamily B, polypeptide 1), which converts 25-hydroxyvitamin D into calcitriol (138)(139)(140) Fgf23 null Fibroblast growth factor-23 (FGF23) (395,626) Gcm2 null Transcription factor glial cells missing (Gcm2), absence of which leads to loss of parathyroids (238,384,385,623,691) Gp130 null Glycoprotein 130 is a transmembrane protein and a receptor subunit common to many cytokines; it interacts with PTH (616,753) Hoxa3 null Homeobox a3 ablation causes abnormalities in tissues derived from the third and fourth pharyngeal arches: loss of parathyroids and thymus, hypoplasia of the thyroid, loss of hyoid, and structural weakness in major arteries that lead hemorrhage at birth (114,336,341,411) Phex null Phex (phosphate regulating endopeptidase homolog, X-linked) encodes an endopeptidase; an inactivating mutation in the gene leads to elevated FGF23 and models X-linked hypophosphatemic rickets (395,484,627). These are also known as Hyp mice due to the hypophosphatemia Pth null Parathyroid hormone (PTH) (310,439,440,623) Pth/Cyp27b1 Double-mutant lacking PTH and calcitriol (747,…”

“…However, its effect during fetal development appears relatively insignificant because Fgf23 null fetuses had no change in serum calcitriol or the renal and placental expression of Cyp27b1 (395); however, Fgf23 null fetuses did have modest but significantly reduced renal expression of Cyp24a1 (395). Conversely, 11-fold increased FGF23 in Phex null male fetuses did cause a small but statistically significant decrease in serum calcitriol, and this was accompanied by significantly increased expression of Cyp24a1 in placenta and fetal kidneys but no change in the expression of Cyp27b1 (395).…”

“…Murine fetuses express FGF23 as early as embryonic day 12.5 in heart, liver, and somites; it later appears in bone (627). Using the sensitive method of real-time quantitative RT-PCR, comparative study of WT, Fgf23 null, and Phex null placentas revealed that the murine placenta expresses a low level of Fgf23 mRNA, which is absent in Fgf23 null placentas but increased in Phex null placentas (395). An independent study used the less sensitive method of conventional RT-PCR and did not find visible Fgf23 amplification on an agarose gel (484).…”