Murine Fetal Serum Phosphorus is Set Independent of FGF23 and PTH, Except in the Presence of Maternal Phosphate Loading

Abstract Fibroblast growth factor 23 (FGF23) appears to play no role until after birth, given unaltered phosphate and bone metabolism in Fgf23- and Klotho-null fetuses. However, in those studies maternal serum phosphorus was normal. We studied whether maternal phosphate loading alters fetal serum phosphorus and invokes a fetal FGF23 or parathyroid hormone (PTH) response. C57BL/6 wild-type (WT) female mice received low (0.3%), normal (0.7%), or high (1.65%) phosphate diets beginning 1 week prior to mating to WT males. Fgf23+/- female mice received the normal or high-phosphate diets 1 week before mating to Fgf23+/- males. One day before expected birth, we harvested maternal and fetal blood, intact fetuses, placentas, and fetal kidneys. Increasing phosphate intake in WT resulted in progressively higher maternal serum phosphorus and FGF23 during pregnancy, while PTH remained undetectable. Fetal serum phosphorus was independent of the maternal phosphorus and PTH remained low, but FGF23 showed a small nonsignificant increase with high maternal serum phosphorus. There were no differences in fetal ash weight and mineral content, or placental gene expression. High phosphate intake in Fgf23+/- mice also increased maternal serum phosphorus and FGF23, but there was no change in PTH. WT fetuses remained unaffected by maternal high-phosphate intake, while Fgf23-null fetuses became hyperphosphatemic but had no change in PTH, skeletal ash weight or mineral content. In conclusion, fetal phosphate metabolism is generally regulated independently of maternal serum phosphorus and fetal FGF23 or PTH. However, maternal phosphate loading reveals that fetal FGF23 can defend against the development of fetal hyperphosphatemia.

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Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling

10.1101/2021.10.22.465390 ◽

2021 ◽

Author(s):

Brian Czaya ◽

Kylie Heitman ◽

Isaac Campos ◽

Christopher Yanucil ◽

Dominik Kentrup ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Wasting ◽

Genetic Disorders ◽

Fibroblast Growth Factor 23 ◽

Kidney Injury ◽

Hepcidin Expression ◽

Phosphate Intake ◽

Skeletal Muscle Wasting ◽

High Phosphate

Elevations in plasma phosphate concentrations (hyperphosphatemia) occur in chronic kidney disease (CKD), in certain genetic disorders, and following the intake of a phosphate-rich diet. Whether hyperphosphatemia and/or associated changes in metabolic regulators, including elevations of fibroblast growth factor 23 (FGF23) directly contribute to specific complications of CKD is uncertain. Here we report that similar to patients with CKD, mice with adenine-induced CKD develop inflammation, anemia and skeletal muscle wasting. These complications are also observed in mice fed high phosphate diet even without CKD. Ablation of pathologic FGF23-FGFR4 signaling did not protect mice on an increased phosphate diet or mice with adenine-induced CKD from these sequelae. However, low phosphate diet ameliorated anemia and skeletal muscle wasting in a genetic mouse model of CKD. Our mechanistic in vitro studies indicate that phosphate elevations induce inflammatory signaling and increase hepcidin expression in hepatocytes, a potential causative link between hyperphosphatemia, anemia and skeletal muscle dysfunction. Our study suggests that high phosphate intake, as caused by the consumption of processed food, may have harmful effects irrespective of pre-existing kidney injury, supporting not only the clinical utility of treating hyperphosphatemia in CKD patients but also arguing for limiting phosphate intake in healthy individuals.

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Fetal Serum Phosphorus is Set Independently of Maternal Serum Phosphorus and Phosphorus Intake

Canadian Journal of Diabetes ◽

10.1016/j.jcjd.2018.08.097 ◽

2018 ◽

Vol 42 (5) ◽

pp. S34

Author(s):

K. Berit Sellars ◽

Brittany A. Ryan ◽

Beth J. Kirby ◽

Christopher S. Kovacs

Keyword(s):

Maternal Serum ◽

Serum Phosphorus ◽

Fetal Serum ◽

Phosphorus Intake

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Renal Dnase1 expression is regulated by FGF23 but loss of Dnase1 does not alter renal phosphate handling

Scientific Reports ◽

10.1038/s41598-021-84735-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Daniela Egli-Spichtig ◽

Martin Y. H. Zhang ◽

Alfred Li ◽

Eva Maria Pastor Arroyo ◽

Nati Hernando ◽

...

Keyword(s):

Mrna Expression ◽

Actin Polymerization ◽

Fibroblast Growth Factor 23 ◽

Wild Type ◽

Vitamin D Metabolism ◽

Endocrine Hormone ◽

Dnase 1 ◽

Sodium Dependent ◽

Renal Tubular ◽

High Phosphate

AbstractFibroblast growth factor 23 (FGF23) is a bone-derived endocrine hormone that regulates phosphate and vitamin D metabolism. In models of FGF23 excess, renal deoxyribonuclease 1 (Dnase1) mRNA expression is downregulated. Dnase-1 is an endonuclease which binds monomeric actin. We investigated whether FGF23 suppresses renal Dnase-1 expression to facilitate endocytic retrieval of renal sodium dependent phosphate co-transporters (NaPi-IIa/c) from the brush border membrane by promoting actin polymerization. We showed that wild type mice on low phosphate diet and Fgf23−/− mice with hyperphosphatemia have increased renal Dnase1 mRNA expression while in Hyp mice with FGF23 excess and hypophosphatemia, Dnase1 mRNA expression is decreased. Administration of FGF23 in wild type and Fgf23−/− mice lowered Dnase1 expression. Taken together, our data shows that Dnase1 is regulated by FGF23. In 6-week-old Dnase1−/− mice, plasma phosphate and renal NaPi-IIa protein were significantly lower compared to wild-type mice. However, these changes were transient, normalized by 12 weeks of age and had no impact on bone morphology. Adaptation to low and high phosphate diet were similar in Dnase1−/− and Dnase1+/+ mice, and loss of Dnase1 gene expression did not rescue hyperphosphatemia in Fgf23−/− mice. We conclude that Dnase-1 does not mediate FGF23-induced inhibition of renal tubular phosphate reabsorption.

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Disruption of Four-and-a-Half LIM 2 Decreases Bone Mineral Content and Bone Mineral Density in Femur and Tibia Bones of Female Mice

Calcified Tissue International ◽

10.1007/s00223-006-0074-7 ◽

2006 ◽

Vol 79 (2) ◽

pp. 112-117 ◽

Cited By ~ 13

Author(s):

K. E. Govoni ◽

D. J. Baylink ◽

J. Chen ◽

S. Mohan

Keyword(s):

Bone Mineral Density ◽

Bone Mineral Content ◽

Bone Mineral ◽

Mineral Content ◽

Mineral Density ◽

Female Mice

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HLA-G Antigen and Parturition: Maternal Serum, Fetal Serum and Amniotic Fluid Levels during Pregnancy

Fetal Diagnosis and Therapy ◽

10.1159/000078992 ◽

2004 ◽

Vol 19 (5) ◽

pp. 404-409 ◽

Cited By ~ 35

Author(s):

Rinat Hackmon ◽

Mordechai Hallak ◽

Margalit Krup ◽

Dahlia Weitzman ◽

Eyal Sheiner ◽

...

Keyword(s):

Amniotic Fluid ◽

Maternal Serum ◽

Fetal Serum ◽

Fluid Levels

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Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin

Kidney International ◽

10.1038/ki.2009.83 ◽

2009 ◽

Vol 75 (12) ◽

pp. 1297-1307 ◽

Cited By ~ 148

Author(s):

Mohga M. El-Abbadi ◽

Ashwini S. Pai ◽

Elizabeth M. Leaf ◽

Hsueh-Ying Yang ◽

Bryan A. Bartley ◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Serum Phosphorus ◽

Fibroblast Growth ◽

Arterial Medial Calcification ◽

Medial Calcification

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Ontogeny of tissue and serum gastrin concentrations in fetal and neonatal sheep

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1981.241.3.g235 ◽

1981 ◽

Vol 241 (3) ◽

pp. G235-G241

Author(s):

L. M. Lichtenberger ◽

S. S. Crandell ◽

P. A. Palma ◽

F. H. Morriss

Keyword(s):

Serum Gastrin ◽

Molecular Form ◽

Cell Number ◽

Maternal Serum ◽

Hormone Concentration ◽

Indwelling Catheters ◽

G Cell ◽

Fetal Serum ◽

Serum Hormone ◽

Serum Gastrin Concentration

We investigated the perinatal ontogenic changes in ovine serum and tissue gastrin concentration. Fetal and maternal serum gastrin levels in serums obtained from indwelling catheters in the fetal and maternal circulations and tissue gastrin levels were assessed by radioimmunoassay and immunohistochemistry. Fetal serum gastrin concentration was undetectable until the 107th day of gestation and significantly increased to levels surpassing maternal values. Neonatal serum hormone concentration continued to rise, reaching a peak during the 4th postnatal wk and decreasing after the 4th wk coincident with weaning. Maternal serum gastrin concentration did not vary during pregnancy and did not correlate with fetal serum gastrin levels. Fetal abomasal and duodenal gastrin concentrations and abomasal G-cell number increased in parallel with the developmental alterations in fetal serum hormone levels during gestation. The developmental increase in abomasal gastrin concentration was not associated with a shift in the molecular form of the hormone. These findings support the hypothesis that circulating gastrin in the fetus is of fetal origin.

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Umbilical cord levels of sclerostin, placental weight, and birth weight are predictors of total bone mineral content in neonates

Acta Endocrinologica ◽

10.1530/eje-12-0531 ◽

2013 ◽

Vol 168 (3) ◽

pp. 371-378 ◽

Cited By ~ 13

Author(s):

Kristin Godang ◽

Kathrine Frey Frøslie ◽

Tore Henriksen ◽

Gunhild A Isaksen ◽

Nanna Voldner ◽

...

Keyword(s):

Birth Weight ◽

Bone Mineral Content ◽

Umbilical Cord ◽

Bone Mineral ◽

Mineral Content ◽

Skeletal Development ◽

Fibroblast Growth Factor 23 ◽

Wnt Signaling Pathway ◽

Placental Weight ◽

Main Role

ContextDuring pregnancy, changes occur in the maternal calcium homeostasis to fulfill fetal demand. We hypothesized that the fibroblast growth factor 23 (FGF23) system and Wnt signaling pathway are important for normal skeletal development in the offspring.AimsCirculating α-klotho, FGF23, sclerostin, and 25-hydroxyvitamin D (25(OH)D) at the fetal and maternal sides of the placenta were measured to investigate associations with newborn bone mass independent of maternal BMI, calcium and phosphate levels, placental weight, and birth weight.MethodsIn a prospective cohort of healthy pregnant women, the total body bone mineral content (BMC) in 202 newborns was measured by dual-energy X-ray absorptiometry. Maternal circulating levels of the biomarkers were measured at gestational weeks 30–32 and in umbilical cord plasma (UCP) at birth.ResultsMean α-klotho and sclerostin concentrations in the UCP were significantly higher than maternal levels (3004 vs 1077 pg/ml;P<0.001 and 629 vs 346 pg/ml;P<0.001 respectively), and mean 25(OH)D was lower (31 vs 45 nmol/l;P<0.001). The UCP and maternal FGF23 levels were similar. No significant effects of maternal biomarkers on BMC were found in regression analyses. Among UCP biomarkers, only UCP sclerostin was significantly associated with BMC in univariate analyses, and the effect remained significant after adjustment for birth weight and other confounders.ConclusionsWe found that UCP sclerostin levels, birth weight, and placental weight were significant predictors of neonatal BMC but found no evidence for a main role of maternal levels of α-klotho, FGF23, sclerostin, or 25(OH)D nor of UCP levels of α-klotho, FGF23, or 25(OH)D.

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