Increased maternofetal calcium flux in parathyroid hormone-related protein-null mice

• Published in: The Journal of physiology Vol. 586; no. 7; pp. 2015 - 2025
• Main Authors: Bond, H., Dilworth, M. R., Baker, B., Cowley, E., Requena Jimenez, A, Boyd, R. D. H., Husain, S. M., Ward, B. S., Sibley, C. P., Glazier, J. D.
• Format: Journal Article
• Language: English
• Published: Oxford, UK The Physiological Society 01.04.2008; Blackwell Publishing Ltd; Blackwell Science Inc
• Subjects: Animals; Biological Transport - physiology; Calbindins; Calcium - metabolism; Female; Fetus - metabolism; Homeostasis - physiology; Integrative; Male; Maternal-Fetal Exchange - physiology; Mice; Mice, Knockout; Parathyroid Hormone-Related Protein - genetics; Parathyroid Hormone-Related Protein - metabolism; Placenta - metabolism; Placental Circulation - physiology; Pregnancy; Pregnancy, Animal - metabolism; S100 Calcium Binding Protein G - metabolism
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2007.149104

The role of parathyroid hormone-related protein (PTHrP) in fetal calcium homeostasis and placental calcium transport was examined in mice homozygous for the deletion of the PTHrP gene ( PTHrP −/− null; NL) compared to PTHrP +/+ (wild-type; WT) and PTHrP +/− (heterozygous; HZ) littermates. Fetal blood ionized calcium was significantly reduced in NL fetuses compared to WT and HZ groups at 18 days of pregnancy (dp) with abolition of the fetomaternal calcium gradient. In situ placental perfusion of the umbilical circulation at 18 dp was used to measure unidirectional clearance of 45 Ca across the placenta in maternofetal ( Ca K mf ) and fetoplacental ( Ca K fp ) directions; Ca K fp was < 5% of Ca K mf for all genotypes. At 18 dp, Ca K mf across perfused placenta and intact placenta ( Ca K mf(intact) ) were similar and concordant with net calcium accretion rates in vivo . Ca K mf was significantly raised in NL fetuses compared to WT and HZ littermates. Calcium accretion was significantly elevated in NL fetuses by 19 dp. Placental calbindin-D 9K expression in NL fetuses was marginally enhanced ( P < 0.07) but expression of TRPV6/ECaC2 and plasma membrane Ca 2+ -ATPase (PMCA) isoforms 1 and 4 were unaltered. We conclude that PTHrP is an important regulator of fetal calcium homeostasis with its predominant effect being on unidirectional maternofetal transfer, probably mediated by modifying placental calbindin-D 9K expression. In situ perfusion of mouse placenta is a robust methodology for allowing detailed dissection of placental transfer mechanisms in genetically modified mice.