Publications (19)78.59 Total impact
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Article: Upregulation of calcitriol during pregnancy and skeletal recovery after lactation do not require parathyroid hormone.
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ABSTRACT: Pregnancy invokes a doubling of intestinal calcium absorption while lactation programs skeletal resorption to provide calcium to milk. Post-weaning bone formation restores the skeleton's bone mineral content (BMC), but the factors that regulate this are not established. We used Pth null mice to test whether parathyroid hormone (PTH) is required for post-weaning skeletal recovery. On a normal 1% calcium diet, WT and Pth null mice each gained BMC during pregnancy, declined 15-18% below baseline during lactation, and restored the skeleton above baseline BMC within 14 days post-weaning. A 2% calcium diet reduced the lactational decline in BMC without altering the gains achieved during pregnancy and post-weaning. The hypocalcemia and hyperphosphatemia of Pth null mice normalized during lactation and serum calcium remained normal during post-weaning. Osteocalcin and P1NP each rose significantly after lactation to similar values in WT and Pth null. Serum calcitriol increased 5-fold during pregnancy in both genotypes while vitamin D binding protein levels were unchanged. Absence of PTH blocked a normal rise in fibroblast growth factor-23 (FGF23) during pregnancy despite high calcitriol. A 30-fold higher expression of Cyp27b1 in maternal kidneys vs. placenta suggests that the pregnancy-related increase in calcitriol comes from the kidneys. Conversely, substantial placental expression of Cyp24a1 may contribute significantly to the metabolism of calcitriol. In conclusion, PTH is not required to upregulate renal expression of Cyp27b1 during pregnancy or to stimulate recovery from loss of BMC caused by lactation. A calcium-rich diet in rodents suppresses skeletal losses during lactation, unlike clinical trials which showed no effect of supplemental calcium on lactational decline in BMC. © 2013 American Society for Bone and Mineral Research.Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2013; · 6.04 Impact Factor -
Article: Lactating Ctcgrp Nulls Lose Twice the Normal Bone Mineral Content due to Fewer Osteoblasts and More Osteoclasts, Whereas Bone Mass Is Fully Restored After Weaning in Association With Up-Regulation of Wnt Signaling and Other Novel Genes.
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ABSTRACT: The maternal skeleton resorbs during lactation to provide calcium to milk and the lost mineral content is restored after weaning. The changes are particularly marked in Ctcgrp null mice, which lose 50% of spine mineral content during lactation but restore it fully. The known calciotropic hormones are not required for skeletal recovery to occur; therefore, unknown factors that stimulate bone formation may be responsible. We hypothesized that the genes responsible for regulating postweaning bone formation are differentially regulated in bone or marrow, and this regulation may be more marked in Ctcgrp null mice. We confirmed that Ctcgrp null mice had twice as many osteoclasts and 30-40% fewer osteoblasts as compared with wild-type mice during lactation but no deficit in osteoblast numbers after weaning. Genome-wide microarray analyses on tibial RNA showed differential expression of 729 genes in wild-type mice at day 7 after weaning vs prepregnancy, whereas the same comparison in Ctcgrp null mice revealed only 283 genes. Down-regulation of Wnt family inhibitors, Sost and Dkk1, and inhibition of Mef2c, a sclerostin stimulator, were observed. Ctsk, a gene expressed during osteoclast differentiation, and Igfbp2, which stimulates bone resorption, were inhibited. Differential regulation of genes involved in energy use was compatible with a net increase in bone formation. The most marked changes occurred in genes not previously associated with bone metabolism. In conclusion, the postlactation skeleton shows dynamic activity with more than 700 genes differentially expressed. Some of these genes are likely to promote bone formation during postweaning by stimulating the proliferation and activity of osteoblasts, inhibiting osteoclasts, and increasing energy use.Endocrinology 03/2013; · 4.46 Impact Factor -
Article: Calcium and bone metabolism disorders during pregnancy and lactation.
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ABSTRACT: Pregnancy and lactation cause a substantial increase in demand for calcium that is met by different maternal adaptations within each period. Intestinal calcium absorption more than doubles during pregnancy, whereas the maternal skeleton resorbs to provide most of the calcium content of breast milk during lactation. These maternal adaptations also affect the presentation, diagnosis, and management of disorders of calcium and bone metabolism. Although some women may experience fragility fractures as a consequence of pregnancy or lactation, for most women, parity and lactation do not affect the long-term risks of low bone density, osteoporosis, or fracture.Endocrinology and metabolism clinics of North America 12/2011; 40(4):795-826. · 3.56 Impact Factor -
Article: Bone development in the fetus and neonate: role of the calciotropic hormones.
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ABSTRACT: During embryonic and fetal development much of the skeleton initiates as a cartilaginous scaffold, which is progressively resorbed and replaced by bone. Endochondral bone formation continues until the growth plates fuse during puberty. At all life stages adequate delivery of mineral is required for the skeleton to achieve and maintain appropriate mineral content and strength. During fetal development the placenta actively transports calcium, phosphorus, and magnesium. Postnatally passive and then active absorption from the intestines becomes the main supply of minerals to the skeleton. Animal and human data indicate that fetal bone development requires parathyroid hormone (PTH) and PTH-related protein but not vitamin D/calcitriol, calcitonin, or (possibly) sex steroids. During the postnatal period, when intestinal calcium absorption becomes an active process, skeletal development begins to depend upon vitamin D/calcitriol but this requirement can be bypassed by increasing the calcium content of the diet or by administering intermittent calcium infusions.Current Osteoporosis Reports 09/2011; 9(4):274-83. -
Article: Skeletal recovery after weaning does not require PTHrP.
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ABSTRACT: Mice lose 20% to 25% of trabecular bone mineral content (BMC) during lactation and restore it after weaning through unknown mechanisms. We found that tibial Pthrp mRNA expression was upregulated fivefold by 7 days after weaning versus end of lactation in wild-type (WT) mice. To determine whether parathyroid hormone-related protein (PTHrP) stimulates bone formation after weaning, we studied a conditional knockout in which PTHrP is deleted from preosteoblasts and osteoblasts by collagen I promoter-driven Cre (Cre(ColI) ). These mice are osteopenic as adults but have normal serum calcium, calcitriol, and parathyroid hormone (PTH). Pairs of Pthrp(flox/flox) ;Cre(ColI) (null) and WT;Cre(ColI) (WT) females were mated and studied through pregnancy, lactation, and 3 weeks of postweaning recovery. By end of lactation, both genotypes lost lumbar spine BMC: WT declined by 20.6% ± 3.3%, and null decreased by 22.5% ± 3.5% (p < .0001 versus baseline; p = NS between genotypes). During postweaning recovery, both restored BMC to baseline: WT to -3.6% ± 3.7% and null to 0.3% ± 3.7% (p = NS versus baseline or between genotypes). Similar loss and full recovery of BMC were seen at the whole body and hind limb. Histomorphometry confirmed that nulls had lower bone mass at baseline and that this was equal to the value achieved after weaning. Osteocalcin, propeptide of type 1 collagen (P1NP), and deoxypyridinoline increased equally during recovery in WT and null mice; PTH decreased and calcitriol increased equally; serum calcium was unchanged. Urine calcium increased during recovery but remained no different between genotypes. Although osteoblast-derived PTHrP is required to maintain adult bone mass and Pthrp mRNA upregulates in bone after weaning, it is not required for recovery of bone mass after lactation. The factors that stimulate postweaning bone formation remain unknown.Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 02/2011; 26(6):1242-51. · 6.04 Impact Factor -
Article: Pregnancy up-regulates intestinal calcium absorption and skeletal mineralization independently of the vitamin D receptor.
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ABSTRACT: Without the vitamin D receptor (VDR), adult mammals develop reduced intestinal calcium absorption, rickets, and osteomalacia. Intestinal calcium absorption normally increases during pregnancy so that the mother can supply sufficient calcium to her fetuses. The maternal skeleton is rapidly resorbed during lactation to provide calcium needed for milk; that lost bone mineral content (BMC) is completely restored after weaning. We studied Vdr null mice to determine whether these adaptations during pregnancy and lactation require the VDR. Vdr nulls were severely rachitic at 10 wk of age on a normal diet. Pregnancy induced a 158% increase in Vdr null BMC to equal the pregnant wild-type (WT) value. Lactation caused BMC losses that were equal in Vdr nulls and WT. Vdr nulls recovered after weaning to a BMC 50% higher than before pregnancy and equal to WT. Additional analyses showed that during pregnancy, duodenal (45)Ca absorption increased in Vdr nulls, secondary hyperparathyroidism lessened, bone turnover markers decreased, and osteoid became fully mineralized. A genome-wide microarray analysis of duodenal RNA found marked reduction of Trpv6 in Vdr nulls at baseline but a 13.5-fold increase during pregnancy. Calbindin D-9K (S100g) and Ca(2+)-ATPase (Pmca1) were not altered by pregnancy. Several other solute transporters increased during pregnancy in Vdr nulls. In summary, Vdr nulls adapt to pregnancy by up-regulating duodenal Trpv6 and intestinal (45)Ca absorption, thereby enabling rapid normalization of BMC during pregnancy. These mice lactate normally and fully restore BMC after weaning. Therefore, VDR is not required for the skeletal adaptations during pregnancy, lactation, and after weaning.Endocrinology 03/2010; 151(3):886-95. · 4.46 Impact Factor -
Article: Thymus-associated parathyroid hormone has two cellular origins with distinct endocrine and immunological functions.
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ABSTRACT: In mammals, parathyroid hormone (PTH) is a key regulator of extracellular calcium and inorganic phosphorus homeostasis. Although the parathyroid glands were thought to be the only source of PTH, extra-parathyroid PTH production in the thymus, which shares a common origin with parathyroids during organogenesis, has been proposed to provide an auxiliary source of PTH, resulting in a higher than expected survival rate for aparathyroid Gcm2⁻/⁻ mutants. However, the developmental ontogeny and cellular identity of these "thymic" PTH-expressing cells is unknown. We found that the lethality of aparathyroid Gcm2⁻/⁻ mutants was affected by genetic background without relation to serum PTH levels, suggesting a need to reconsider the physiological function of thymic PTH. We identified two sources of extra-parathyroid PTH in wild-type mice. Incomplete separation of the parathyroid and thymus organs during organogenesis resulted in misplaced, isolated parathyroid cells that were often attached to the thymus; this was the major source of thymic PTH in normal mice. Analysis of thymus and parathyroid organogenesis in human embryos showed a broadly similar result, indicating that these results may provide insight into human parathyroid development. In addition, medullary thymic epithelial cells (mTECs) express PTH in a Gcm2-independent manner that requires TEC differentiation and is consistent with expression as a self-antigen for negative selection. Genetic or surgical removal of the thymus indicated that thymus-derived PTH in Gcm2⁻/⁻ mutants did not provide auxiliary endocrine function. Our data show conclusively that the thymus does not serve as an auxiliary source of either serum PTH or parathyroid function. We further show that the normal process of parathyroid organogenesis in both mice and humans leads to the generation of multiple small parathyroid clusters in addition to the main parathyroid glands, that are the likely source of physiologically relevant "thymic PTH."PLoS Genetics 01/2010; 6(12):e1001251. · 8.69 Impact Factor -
Article: Role of parathyroid hormone (PTH) and PTH-related protein (PTHrP) in regulating mineral homeostasis during fetal development.
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ABSTRACT: Parathyroid hormone (PTH) and PTH-related protein (PTHrP) play complementary and overlapping roles in regulating fetal mineral homeostasis. PTHrP is expressed within the growth plate, directs endochondral bone formation, and determines the fate of chondrocytes before bone formation can be initiated. It is expressed in placenta and is present at high levels in the fetal circulation. It stimulates placental calcium (and possibly magnesium) transfer and raises blood mineral levels above ambient maternal values in order to effect mineralization of the skeleton. It does not upregulate in response to absence of PTH or hypocalcemia, and thus, its secretion may be regulated autonomously or in response to placental signals. PTH is expressed in fetal parathyroids and placenta. Despite circulating at low levels, it has a more dominant effect than PTHrP in regulating the blood calcium and ensuring adequate mineralization of the skeleton. It may also have effects on bone formation in the steps that occur after apoptosis of hypertrophic chondrocytes. Unlike PTHrP, it increases with fetal hypocalcemia, but its secretion is constrained by the calcium-sensing receptor to maintain the adult calcium level, well below what the fetus normally achieves. PTH also stimulates placental calcium transfer, and its absence disrupts placental expression of calciotropic and cation transporter genes.Critical Reviews in Eukaryotic Gene Expression 01/2010; 20(3):235-73. · 3.08 Impact Factor -
Article: Parathyroid hormone regulates fetal-placental mineral homeostasis.
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ABSTRACT: Parathyroid hormone (PTH) plays an essential role in regulating calcium and bone homeostasis in the adult, but whether PTH is required at all for regulating fetal-placental mineral homeostasis and skeletal development is uncertain. We hypothesized that despite its low circulating levels during fetal life, PTH plays a critical role in regulating these processes. To address this, we examined two different genetic models of PTH deficiency. Pth null mice have enlarged parathyroids that are incapable of making PTH, whereas Gcm2 null mice lack parathyroids but have PTH that arises from the thymus. Pth nulls served as a model of complete absence of PTH, whereas Gcm2 nulls were a model of severe hypoparathyroidism. We determined that PTH contributes importantly to fetal mineral homeostasis because in its absence a fetal hypoparathyroid phenotype results with hypocalcemia, hypomagnesemia, hyperphosphatemia, low amniotic fluid mineral content, and reduced skeletal mineral content. We also determined that PTH is expressed in the placenta, regulates the placental expression of genes involved in calcium and other solute transfer, and may directly stimulate placental calcium transfer. Although parathyroid hormone-related protein (PTHrP) acts in concert with PTH to regulate fetal mineral homeostasis and placental calcium transfer, unlike PTH, it does not upregulate in response to fetal hypocalcemia.Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 09/2009; 25(3):594-605. · 6.04 Impact Factor -
Article: Hemophilia, low bone mass, and osteopenia/osteoporosis.
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ABSTRACT: A recent case series from Australia suggested that children with hemophilia may be more likely to have low bone density or osteopenia than healthy controls. This finding has led to uncertainty among patients and their physicians as to whether treatment with bisphosphonates is indicated to treat osteopenia and prevent osteoporosis in children or young adults with hemophilia. In fact, several studies confirmed that selected patients with hemophilia were shorter, weighed less, had reduced physical activity, and had other factors (hepatitis C and HIV seropositivity) which predict lower peak bone mass. Some of these factors may accelerate loss of bone mass between ages 20 and 50 when bone mass should otherwise be stable, but no study has yet confirmed if this is the case for patients with hemophilia. Treatment with weight-bearing physical activity, physiotherapy and surgery to remobilize diseased joints, and calcium and vitamin D supplementation, can be recommended for anyone at any age. Treatment with an antiresorptive medication (usually a bisphosphonate) is not indicated for low peak bone mass that will otherwise be maintained by the patient between ages 20 and 50. On the other hand, on an individualized basis, treatment with an antiresorptive may be indicated for patients in whom rapid loss of bone mass has been confirmed by sequential BMD measurements, or who have already suffered fragility fractures, or who have reached an age and BMD value that places them into a high-risk category for estimated 10-year fracture risk.Transfusion and Apheresis Science 03/2008; 38(1):33-40. · 1.25 Impact Factor -
Article: Calcitonin plays a critical role in regulating skeletal mineral metabolism during lactation.
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ABSTRACT: The maternal skeleton rapidly demineralizes during lactation to provide calcium to milk, responding to the stimuli of estrogen deficiency and mammary-secreted PTH-related protein. We used calcitonin/calcitonin gene-related peptide-alpha (Ctcgrp) null mice to determine whether calcitonin also modulates lactational mineral metabolism. During 21 d of lactation, spine bone mineral content dropped 53.6% in Ctcgrp nulls vs. 23.6% in wild-type (WT) siblings (P < 0.0002). After weaning, bone mineral content returned fully to baseline in 18.1 d in Ctcgrp null vs. 13.1 d in WT (P < 0.01) mice. Daily treatment with salmon calcitonin from the onset of lactation normalized the losses in Ctcgrp null mice, whereas calcitonin gene-related peptide-alpha or vehicle was without effect. Compared with WT, Ctcgrp null mice had increased circulating levels of PTH and up-regulation of mammary gland PTH-related protein mRNA. In addition, lactation caused the Ctcgrp null skeleton to undergo more trabecular thinning and increased trabecular separation compared with WT. Our studies confirm that an important physiological role of calcitonin is to protect the maternal skeleton against excessive resorption and attendant fragility during lactation and reveal that the postweaning skeleton has the remarkable ability to rapidly recover even from losses of over 50% of skeletal mineral content.Endocrinology 09/2006; 147(9):4010-21. · 4.46 Impact Factor -
Article: Calcium and bone disorders during pregnancy and lactation.
Endocrinology & Metabolism Clinics of North America 04/2006; 35(1):21-51, v. · 3.41 Impact Factor -
Article: The vitamin D receptor is not required for fetal mineral homeostasis or for the regulation of placental calcium transfer in mice.
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ABSTRACT: We utilized a vitamin D receptor (VDR) gene knockout model to study the effects of maternal and fetal absence of VDR on maternal fertility, fetal-placental calcium transfer, and fetal mineral homoeostasis. Vdr null mice were profoundly hypocalcemic, conceived infrequently, and had significantly fewer viable fetuses in utero that were also of lower body weight. Supplementation of a calcium-enriched diet increased the rate of conception in Vdr nulls but did not normalize the number or weight of viable fetuses. Among offspring of heterozygous (Vdr(+/-)) mothers (wild type, Vdr(+/-), and Vdr null fetuses), there was no alteration in serum Ca, P, or Mg, parathyroid hormone, placental (45)Ca transfer, Ca and Mg content of the fetal skeleton, and morphology and gene expression in the fetal growth plates. Vdr null fetuses did have threefold increased 1,25-dihydroxyvitamin D levels accompanied by increased 1alpha-hydroxylase mRNA in kidney but not placenta; a small increase was also noted in placental expression of parathyroid hormone-related protein (PTHrP). Among offspring of Vdr null mothers, Vdr(+/-) and Vdr null fetuses had normal ionized calcium levels and a skeletal ash weight that was appropriate to the lower body weight. Thus our findings indicate that VDR is not required by fetal mice to regulate placental calcium transfer, circulating mineral levels, and skeletal mineralization. Absence of maternal VDR has global effects on fetal growth that were partly dependent on maternal calcium intake, but absence of maternal VDR did not specifically affect fetal mineral homeostasis.AJP Endocrinology and Metabolism 08/2005; 289(1):E133-44. · 4.75 Impact Factor -
Article: Calcium and bone metabolism during pregnancy and lactation.
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ABSTRACT: Pregnancy and lactation both place significant demands on the mother to provide sufficient calcium (among other minerals and nutrients) to the fetus and neonate. Despite facing similar demands for calcium during pregnancy and lactation, the maternal adaptations differ significantly between these two reproductive periods. Women lose 300 to 400 mg of calcium daily through breast milk, and this calcium demand is met by a 5-10% loss of skeletal mineral content during 6 months of exclusive lactation. Most importantly, the lost mineral is fully restored within a few months of weaning, such that women who have breastfed do not have a long-term deficit in skeletal mineral content. This article will review our present understanding of the adaptations in mineral metabolism that occur during pregnancy and lactation, and will focus on recent evidence that the breast itself plays a central role in regulating the adaptations during lactation.Journal of Mammary Gland Biology and Neoplasia 05/2005; 10(2):105-18. · 6.74 Impact Factor -
Article: Ablation of calcitonin/calcitonin gene-related peptide-alpha impairs fetal magnesium but not calcium homeostasis.
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ABSTRACT: We used the calcitonin/calcitonin gene-related peptide (CGRP)-alpha gene knockout model (Ct/Cgrp null) to determine whether calcitonin and CGRPalpha are required for normal fetal mineral homeostasis and placental calcium transfer. Heterozygous (Ct/Cgrp(+/-)) and Ct/Cgrp null females were mated to Ct/Cgrp(+/-) males. One or two days before term, blood was collected from mothers and fetuses and analyzed for ionized Ca, Mg, P, parathyroid hormone (PTH), and calcitonin. Amniotic fluid was collected for Ca, Mg, and P. To quantify skeletal mineral content, fetuses were reduced to ash, dissolved in nitric acid, and analyzed by atomic absorption spectroscopy for total Ca and Mg. Placental transfer of (45)Ca at 5 min was assessed. Ct/Cgrp null mothers had significantly fewer viable fetuses in utero compared with Ct/Cgrp(+/-) and wild-type mothers. Fetal serum Ca, P, and PTH did not differ by genotype, but serum Mg was significantly reduced in null fetuses. Placental transfer of (45)Ca at 5 min was normal. The calcium content of the fetal skeleton was normal; however, total Mg content was reduced in Ct/Cgrp null skeletons obtained from Ct/Cgrp null mothers. In summary, maternal absence of calcitonin and CGRPalpha reduced the number of viable fetuses. Fetal absence of calcitonin and CGRPalpha selectively reduced serum and skeletal magnesium content but did not alter ionized calcium, placental calcium transfer, and skeletal calcium content. These findings indicate that calcitonin and CGRPalpha are not needed for normal fetal calcium metabolism but may regulate aspects of fetal Mg metabolism.AJP Endocrinology and Metabolism 09/2004; 287(2):E218-26. · 4.75 Impact Factor -
Article: Arrested pulmonary alveolar cytodifferentiation and defective surfactant synthesis in mice missing the gene for parathyroid hormone-related protein.
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ABSTRACT: Parathyroid hormone-related protein (PTHrP) and PTH/PTHrP receptor expression are developmentally regulated in lung epithelium and adepithelial mesenchyme, respectively. To test the hypothesis that PTHrP is a developmental regulator of terminal airway development, we investigated in vivo and in vitro models of alveolar cytodifferentiation using mice in which the gene encoding PTHrP was ablated by homologous recombination. We have determined that fetal and newborn PTHrP(-/-) lungs showed delayed mesenchymal-epithelial interactions, arrested type II cell differentiation, and reduced surfactant lamellar body formation and pulmonary surfactant production. Embryonic PTHrP(-/-) lung buds cultured in the absence of skeletal constriction or systemic compensating factors also exhibited delayed alveolar epithelial (type II cell) and mesenchymal cytodifferentiation, as well as a > 40% inhibition of surfactant phospholipid production (n = 3-5). Addition of exogenous PTHrP to embryonic PTHrP(-/-) lung cultures normalized interstitial cell morphology and surfactant phospholipid production. The importance of PTHrP as an endogenous regulatory molecule in mammalian lung development is supported by the findings that ablation of PTHrP expression in isolated developing lung is sufficient to disrupt normal development of the alveolar ducts and the centriacinar regions.Developmental Dynamics 06/2004; 230(2):278-89. · 2.54 Impact Factor -
Article: Physiological studies in heterozygous calcium sensing receptor (CaSR) gene-ablated mice confirm that the CaSR regulates calcitonin release in vivo.
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ABSTRACT: The calcium sensing receptor (CaSR) regulates serum calcium by suppressing secretion of parathyroid hormone; it also regulates renal tubular calcium excretion. Inactivating mutations of CaSR raise serum calcium and reduce urine calcium excretion. Thyroid C-cells (which make calcitonin) express CaSR and may, therefore, be regulated by it. Since calcium stimulates release of calcitonin, the higher blood calcium caused by inactivation of CaSR should increase serum calcitonin, unless CaSR mutations alter the responsiveness of calcitonin to calcium. To demonstrate regulatory effects of CaSR on calcitonin release, we studied calcitonin responsiveness to calcium in normal and CaSR heterozygous-ablated (Casr+/-) mice. Casr+/- mice have hypercalcemia and hypocalciuria, and live normal life spans. Each mouse received either 500 microl of normal saline or one of two doses of elemental calcium (500 micromol/kg or 5 mmol/kg) by intraperitoneal injection. Ionized calcium was measured at baseline and 10 minutes, and serum calcitonin was measured on the 10 minute sample. At baseline, Casr+/- mice had a higher blood calcium, and in response to the two doses of elemental calcium, had greater increments and peak levels of ionized calcium than their wild type littermates. Despite significantly higher ionized calcium levels, the calcitonin levels of Casr+/- mice were consistently lower than wild type at any ionized calcium level, indicating that the dose-response curve of calcitonin to increases in ionized calcium had been significantly blunted or shifted to the right in Casr+/- mice. These results confirm that the CaSR is a physiological regulator of calcitonin; therefore, in response to increases in ionized calcium, the CaSR inhibits parathyroid hormone secretion and stimulates calcitonin secretion.BMC Physiology 05/2004; 4:5. -
Article: Novel hexad repeats conserved in a putative transporter with restricted expression in cell types associated with growth, calcium exchange and homeostasis.
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ABSTRACT: A transport protein is described with 12 transmembrane spans. Within the cytoplasmic amino-terminal domain, several novel hexad repeats are conserved in human, mouse, rat and pig, four to six of which had the canonical form PS_S_H(+). In the carboxyl-terminal domain, a polyglutamate sequence (5-8) is conserved. Restricted expression of the transporter was identified in acidophil cells of the adult pituitary that secrete growth hormone and prolactin. In the fetus, expression was restricted to osteoclasts, chondrocytes, thyroid, pituitary, central nervous system, eye, liver and heart. In particular, expression was found in structures associated with rapid calcium exchange including the retina, cardiomyocytes and in the intraplacental yolk sac that expresses calcitropic molecules. Furthermore, expression found in osteoclasts and kidney, within the distal portions of nephrons and collecting ducts, was consistent with a role in calcium homeostasis. In human pituitary, four mRNA transcripts, and in mouse kidney, three mRNA transcripts were expressed. In developing mouse kidney, the amount of each transcript varied that suggested the multiple transcripts might be differentially expressed in different physiological states. We propose that the transporter is specific for a calcium-chelator complex and is important for growth and calcium metabolism.Experimental Cell Research 03/2004; 293(1):31-42. · 3.58 Impact Factor -
Article: Calcitropic gene expression suggests a role for the intraplacental yolk sac in maternal-fetal calcium exchange.
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ABSTRACT: The expression of calcitropic genes and proteins was localized within murine placenta during late gestation (the time frame of active calcium transfer) with an analysis of several gene-deletion mouse models by immunohistochemistry and in situ hybridization. Parathyroid hormone-related protein (PTHrP), the PTH/PTHrP receptor, calcium receptor, calbindin-D(9k), Ca(2+)-ATPase, and vitamin D receptor were all highly expressed in a localized structure of the murine placenta, the intraplacental yolk sac, compared with trophoblasts. In the PTHrP gene-deleted or Pthrp-null placenta in which placental calcium transfer is decreased, calbindin-D(9k) expression was downregulated in the intraplacental yolk sac but not in the trophoblasts. These observations indicated that the intraplacental yolk sac contains calcium transfer and calcium-sensing capability and that it is a probable route of maternal-fetal calcium exchange in the mouse.AJP Endocrinology and Metabolism 04/2002; 282(3):E721-32. · 4.75 Impact Factor
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2002–2011
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Memorial University of Newfoundland
- Faculty of Medicine
Saint John, New Brunswick, Canada
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