Neonatal Iron Deficiency Causes Abnormal Phosphate Metabolism by Elevating FGF23 in Normal and ADHR Mice

Abstract

Fibroblast growth factor 23 (FGF23) gain of function mutations can lead to autosomal dominant hypophosphatemic rickets (ADHR) disease onset at birth, or delayed onset following puberty or pregnancy. We previously demonstrated that the combination of iron deficiency and a knock-in R176Q FGF23 mutation in mature mice induced FGF23 expression and hypophosphatemia that paralleled the late-onset ADHR phenotype. Because anemia in pregnancy and in premature infants is common, the goal of this study was to test whether iron deficiency alters phosphate handling in neonatal life. Wild-type (WT) and ADHR female breeder mice were provided control or iron-deficient diets during pregnancy and nursing. Iron-deficient breeders were also made iron replete. Iron-deficient WT and ADHR pups were hypophosphatemic, with ADHR pups having significantly lower serum phosphate (p < 0.01) and widened growth plates. Both genotypes increased bone FGF23 mRNA (>50 fold; p < 0.01). WT and ADHR pups receiving low iron had elevated intact serum FGF23; ADHR mice were affected to a greater degree (p < 0.01). Iron-deficient mice also showed increased Cyp24a1 and reduced Cyp27b1, and low serum 1,25-dihydroxyvitamin D (1,25D). Iron repletion normalized most abnormalities. Because iron deficiency can induce tissue hypoxia, oxygen deprivation was tested as a regulator of FGF23, and was shown to stimulate FGF23 mRNA in vitro and serum C-terminal FGF23 in normal rats in vivo. These studies demonstrate that FGF23 is modulated by iron status in young WT and ADHR mice and that hypoxia independently controls FGF23 expression in situations of normal iron. Therefore, disturbed iron and oxygen metabolism in neonatal life may have important effects on skeletal function and structure through FGF23 activity on phosphate regulation.

Carboxy-terminal fragment of fibroblast growth factor 23 induces heart hypertrophy in sickle cell disease

“…12 In rats housed under hypobaric atmosphere, cFGF23 plasma concentration increased while iFGF23 concentration was unchanged, 11 which is similar to our observations in SCD patients. In addition, cFGF23, but not iFGF23 plasma concentration, was increased in women with iron deficiency anemia.…”

Iron Supplementation Associated With Loss of Phenotype in Autosomal Dominant Hypophosphatemic Rickets

“…To date, iron supplementation has not been attempted in patients with ADHR. However, elevated FGF23 levels and hypophosphatemia seemed to normalize with iron supplementation in iron-deficient neonatal wild type and ADHR mice in a recent study (21). Here, we demonstrate an association of oral iron (II) supplementation with remission of hypophosphatemia in a girl with ADHR.…”

NFκB-sensitive Orai1 expression in the regulation of FGF23 release

“…FGF23 plasma levels are further modified by iron deficiency [25,26], pregnancy [27] and FGF23 secreting tumors [28].…”