Parathyroid hormone-related peptide (PTHrP) regulates fetal–placental calcium transport through a receptor  distinct from the PTH/PTHrP receptor

Kovacs, Christopher S.; Lanske, Beate; Hunzelman, Joy L.; Guo, Jun; Karaplis, Andrew C.; Kronenberg, Henry M.

doi:10.1073/pnas.93.26.15233

Cited by 301 publications

(228 citation statements)

References 40 publications

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“…1 ]. These data demonstrate that the fetomaternal calcium gradient in these mice is established between E17 and E19, and further suggest that active transplacental calciumtransport mechanisms during this period begin to contribute significantly to maternofetal calcium flux, consistent with other studies in mice and rats (23)(24)(25)(26). In contrast, fetal blood [Ca 2+ ] in P0 was significantly lower than WT and maternal blood at both E17 and E19 (P < 0.05).…”

Section: Resultssupporting

confidence: 67%

“…Therefore, despite the marked growth restriction of the P0 fetuses at both E17 and E19 and a reduced placental mass, skeletal hypomineralization of the P0 fetus at E17 is corrected by E19, and this is achieved by a rise in Ca J mf . Work from several species suggests that active placental calcium transport is switched on, or up-regulated, near to term, as bone mineral accretion begins (23,25,26,(40)(41)(42)(43). The capacity to raise Ca J mf in P0 indicates that the functional integrity of active calcium-transport mechanisms in P0 placentas is preserved.…”

Section: Resultsmentioning

confidence: 99%

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Placental-specific Igf2 knockout mice exhibit hypocalcemia and adaptive changes in placental calcium transport

Dilworth¹,

Kusinski²,

Cowley³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Evidence is emerging that the ability of the placenta to supply nutrients to the developing fetus adapts according to fetal demand. To examine this adaptation further, we tested the hypothesis that placental maternofetal transport of calcium adapts according to fetal calcium requirements. We used a mouse model of fetal growth restriction, the placental-specific Igf2 knockout (P0) mouse, shown previously to transiently adapt placental System-A amino acid transporter activity relative to fetal growth. Fetal and placental weights in P0 mice were reduced when compared with WT at both embryonic day 17 (E17) and E19. Ionized calcium concentration [Ca 2+ ] was significantly lower in P0 fetal blood compared with both WT and maternal blood at E17 and E19, reflecting a reversal of the fetomaternal [Ca 2+ ] gradient. Fetal calcium content was reduced in P0 mice at E17 but not at E19. Unidirectional maternofetal calcium clearance ( Ca K mf ) was not different between WT and P0 at E17 but increased in P0 at E19. Expression of the intracellular calcium-binding protein calbindin-D 9K , previously shown to be rate-limiting for calcium transport, was increased in P0 relative to WT placentas between E17 and E19. These data show an increased placental transport of calcium from E17 to E19 in P0 compared to WT. We suggest that this is an adaptation in response to the reduced fetal calcium accumulation earlier in gestation and speculate that the ability of the placenta to adapt its supply capacity according to fetal demand may stretch across other essential nutrients.fetal growth restriction | calbindin | PMCA | pregnancy

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Section: Resultssupporting

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Placental-specific Igf2 knockout mice exhibit hypocalcemia and adaptive changes in placental calcium transport

Dilworth¹,

Kusinski²,

Cowley³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous studies have clearly documented the indispensable biological importance of PTHrP/PTH1R signaling in skeletal (11)(12)(13)(14)(15) and mammary gland (16,17) development. Additional endocrine and paracrine functions have been ascribed to the mid-region and C-terminal region (107 to 139) of the molecule (18,19). In vitro studies have indicated that PTHrP displays other functions largely relating to an intracrine signaling role in the nucleus/nucleolus (4,20,21) and that its subcellular distribution is cell-cycle dependent (22) in that PTHrP is targeted to the nucleolus of cells in G 1. In the present study, we examined the potential biological relevance of the nuclear localization of PTHrP in vivo by inserting a premature termination codon (TGA) in the murine Pthrp, and generating a ''knock-in'' (KI) mouse expressing PTHrP (1-84), a form of the protein that lacks the NLS and C-terminal region.…”

Section: Ntranuclear Transport Of Numerous Polypeptide Ligands Hasmentioning

confidence: 99%

Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related protein

Miao

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

113

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Parathyroid hormone (PTH) plays a central role in the regulation of serum calcium and phosphorus homeostasis, while parathyroid hormone-related protein (PTHrP) has important developmental roles. Both peptides signal through the same G protein-coupled receptor, the PTH/PTHrP or PTH type 1 receptor (PTH1R). PTHrP, normally a secreted protein, also contains a nuclear localization signal (NLS) that in vitro imparts functionality to the protein at the level of the nucleus. We investigated this functionality in vivo by introducing a premature termination codon in Pthrp in ES cells and generating mice that express PTHrP (1-84), a truncated form of the protein that is missing the NLS and the C-terminal region of the protein but can still signal through its cell surface receptor. Mice homozygous for the knock-in mutation (Pthrp KI) displayed retarded growth, early senescence, and malnutrition leading postnatally to their rapid demise. Decreased cellular proliferative capacity and increased apoptosis in multiple tissues including bone and bone marrow cells were associated with altered expression and subcellular distribution of the senescenceassociated tumor suppressor proteins p16 INK4a and p21 and the oncogenes Cyclin D, pRb, and Bmi-1. These findings provide in vivo experimental proof that substantiates the biologic relevance of the NLS and C-terminal portion of PTHrP, a polypeptide ligand that signals mainly via a cell surface G protein-coupled receptor.ageing ͉ nucleus ͉ osteoporosis ͉ PTHrP ͉ senescence

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“…44,45 During follow-up, the main determinant of plasma PTH was infant body weight, which probably reflects an increased need for calcium with skeletal growth as the infants' own parathyroid glands are taking over following birth. [46][47][48][49] However, our data do not exclude that plasma PTH per se may exert an effect on growth and body weight. Importantly, because of the design of our study, it does not allow for conclusions on cause-effect relationships.…”

Section: Maternal and Infant Vitamin D Status S Vij Streym Et Almentioning

confidence: 99%

Maternal and infant vitamin D status during the first 9 months of infant life—a cohort study

et al. 2013

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BACKGROUND/OBJECTIVES: The objective of this study was to assess vitamin D status and possible consequences of low plasma 25-hydroxyvitamin D (25OHD) levels in a population of healthy mothers and their infants. SUBJECTS/METHODS: A total of 107 women aged 24-41 years gave birth to 108 infants. They were followed up three times during 9 months. RESULTS: Cord blood 25OHD level (43.3 ± 20.4 nmol/l) on average was 62 ± 16% of maternal levels (73.3 ± 30.7 nmol/l), measured 1-2 weeks postpartum. Cord blood 25OHD correlated positively with maternal 25OHD levels (r ¼ 0.83, Po0.001). At birth, 23% of mothers and 61% of infants had 25OHD o50 nmol/l. Vitamin D deficiency (25OHDo25 nmol/l) was present in 66% of the children born by mothers with 25OHD levels below 50 nmol/l (Po0.01), whereas only one child was born with deficiency among mothers with 25OHD 450 nmol/l. During follow-up, most of the children (485%) had 25OHD levels 450 nmol/l, which most likely was attributable to the use of supplements, as more than 95% of the children were given daily vitamin D supplements of 10 mg of vitamin D. Cord blood parathyroid hormone levels were very low (median 0.21; interquartile range 0.11-0.33 pmol/l), with increasing levels (Po0.01) reaching 3.08 (2.67-3.92 pmol/l) at the last visit. Vitamin D levels were not associated with anthropometric indices of the newborn infant or their growth during follow-up. CONCLUSIONS: Vitamin D deficiency is widespread in newborn. Maternal 25OHD levels above 50 nmol/l are needed to prevent vitamin D deficiency among newborn.

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Parathyroid hormone-related peptide (PTHrP) regulates fetal–placental calcium transport through a receptor distinct from the PTH/PTHrP receptor

Cited by 301 publications

References 40 publications

Placental-specific Igf2 knockout mice exhibit hypocalcemia and adaptive changes in placental calcium transport

Placental-specific Igf2 knockout mice exhibit hypocalcemia and adaptive changes in placental calcium transport

Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related protein

Maternal and infant vitamin D status during the first 9 months of infant life—a cohort study

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