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Christopher S Kovacs - One of the best experts on this subject based on the ideXlab platform.

  • Maternal and fetal vitamin D and their roles in Mineral Homeostasis and fetal bone development
    Journal of Endocrinological Investigation, 2021
    Co-Authors: Brittany A. Ryan, Christopher S Kovacs
    Abstract:

    During pregnancy, female physiology adapts to meet the additional Mineral demands of the developing fetus. Meanwhile, the fetus actively transports Minerals across the placenta and maintains high circulating levels to Mineralize the rapidly developing skeleton. Most of this Mineral is accreted during the last trimester, including 30 g of calcium, 20 g of phosphate and 0.8 g of magnesium. Given the dependence of calcium Homeostasis on vitamin D and calcitriol in the adult and child, it may be expected that vitamin D sufficiency would be even more critical during pregnancy and fetal development. However, the pregnant mother and fetus appear to meet their Mineral needs independent of vitamin D. Adaptations in maternal Mineral and bone metabolism during pregnancy appear to be invoked independent of maternal vitamin D, while fetal Mineral metabolism and skeletal development appear to be protected from vitamin D deficiency and genetic disorders of vitamin D physiology. This review discusses key data from both animal models and human studies to address our current knowledge on the role of vitamin D and calcitriol during pregnancy and fetal development.

  • Mineral Homeostasis in Murine Fetuses Is Sensitive to Maternal Calcitriol but Not to Absence of Fetal Calcitriol.
    Journal of Bone and Mineral Research, 2019
    Co-Authors: Brittany A. Ryan, Kamal Alhani, K. Berit Sellars, Beth J. Kirby, Rene Arnaud, Glenville Jones, Martin Kaufmann, Christopher S Kovacs
    Abstract:

    : Vitamin D receptor (VDR) null fetuses have normal serum Minerals, parathyroid hormone (PTH), skeletal morphology, and Mineralization but increased serum calcitriol, placental calcium transport, and placental expression of Pthrp, Trpv6, and (as reported in this study) Pdia3. We examined Cyp27b1 null fetal mice, which do not make calcitriol, to determine if loss of calcitriol has the same consequences as loss of VDR. Cyp27b1 null and wild-type (WT) females were mated to Cyp27b1+/- males, which generated Cyp27b1 null and Cyp27b1+/- fetuses from Cyp27b1 null mothers, and Cyp27b1+/- and WT fetuses from WT mothers. Cyp27b1 null fetuses had undetectable calcitriol but normal serum calcium and phosphorus, PTH, fibroblast growth factor 23 (FGF23), skeletal Mineral content, tibial lengths and morphology, placental calcium transport, and expression of Trpv6 and Pthrp; conversely, placental Pdia3 was downregulated. However, although Cyp27b1+/- and null fetuses of Cyp27b1 null mothers were indistinguishable, they had higher serum and amniotic fluid calcium, lower amniotic fluid phosphorus, lower FGF23, and higher 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D than in WT and Cyp27b1+/- fetuses of WT mothers. In summary, loss of fetal calcitriol did not alter Mineral or bone Homeostasis, but Cyp27b1 null mothers altered Mineral Homeostasis in their fetuses independent of fetal genotype. Cyp27b1 null fetuses differ from Vdr null fetuses, possibly through high levels of calcitriol acting on Pdia3 in Vdr nulls to upregulate placental calcium transport and expression of Trpv6 and Pthrp. In conclusion, maternal calcitriol influences fetal Mineral metabolism, whereas loss of fetal calcitriol does not. © 2018 American Society for Bone and Mineral Research.

  • bone development and Mineral Homeostasis in the fetus and neonate roles of the calciotropic and phosphotropic hormones
    Physical Review, 2014
    Co-Authors: Christopher S Kovacs
    Abstract:

    Mineral and bone metabolism are regulated differently in utero compared with the adult. The fetal kidneys, intestines, and skeleton are not dominant sources of Mineral supply for the fetus. Instead...

  • fetal Mineral Homeostasis
    Pediatric Bone (Second Edition)#R##N#Biology & Diseases, 2012
    Co-Authors: Christopher S Kovacs
    Abstract:

    Publisher Summary Much of normal calcium and bone Homeostasis in the adult can be explained by the interactions of parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (calcitriol), fibroblast growth factor-23 (FGF-23), calcitonin, and the sex steroids. Deficiency of PTH causes potentially fatal hypocalcemia as well as hyperphosphatemia, hypercalciuria, low bone turnover, and basal ganglia calcifications. Many hormones are not required to regulate fetal calcium and bone metabolism. The need of this developmental period include to actively pump calcium (and other Minerals) across the placenta against a concentration gradient, to maintain high extracellular levels of calcium (and other Minerals) compared to the mother, and to Mineralize fully the skeleton by the time of birth. A human fetus typically accumulates 21 g of calcium by term, and 80% of this is obtained in the third trimester with 200–300 mg transported daily across the placenta. Vitamin D deficiency causes more modest hypocalcemia as well as hypophosphatemia and rickets or osteomalacia. Estrogen deficiency causes increased skeletal resorption and osteoporosis. There are three fetal Minerals that are explained briefly, calcium, phosphorus, and magnesium. Maternal hypoparathyroidism in human pregnancy has been associated with the development of intrauterine, fetal hyperparathyroidism. This is characterized by fetal parathyroid gland hyperplasia, generalized skeletal deMineralization, subperiosteal bone resorption, bowing of the long bones, osteitis fibrosa cystica, rib and limb fractures, and low birth weight.

  • Parathyroid hormone regulates fetal-placental Mineral Homeostasis.
    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2010
    Co-Authors: Charlene Simmonds, Gerard Karsenty, Andrew C. Karaplis, Christopher S Kovacs
    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.

Reinhold G Erben - One of the best experts on this subject based on the ideXlab platform.

  • α klotho s effects on Mineral Homeostasis are fibroblast growth factor 23 dependent
    Current Opinion in Nephrology and Hypertension, 2018
    Co-Authors: Reinhold G Erben
    Abstract:

    Purpose of review α-Klotho (Klotho) occurs in three isoforms, a membrane-bound form acting as a coreceptor for fibroblast growth factor-23 (FGF23) signalling, a shed soluble form consisting of Klotho's large ectodomain thought to act as an enzyme or a hormone, and a secreted truncated form generated by alternative splicing of the Klotho mRNA with unknown function. The purpose of this review is to highlight the recent advances in our understanding of Klotho's function in Mineral Homeostasis. Recent findings A number of seminal discoveries have recently been made in this area, shifting existing paradigms. The crystal structure of the ternary FGF receptor (FGFR)-1c/Klotho/FGF23 complex has been uncovered, revealing how the ligand FGF23 interacts with FGFR1c and the coreceptor Klotho at atomic resolution. Furthermore, it was shown that soluble Klotho lacks any glycosidase activity and serves as a bona fide coreceptor for FGF23 signalling. Experiments with a combination of Klotho and Fgf23-deficient mouse models demonstrated that all isoforms of Klotho lack any physiologically relevant, FGF23-independent functions in Mineral Homeostasis or ageing. Finally, it was demonstrated that the alternatively spliced Klotho mRNA is degraded and is not translated into a secreted Klotho protein isoform in humans. Summary Taken together, there is now overwhelming evidence that the main physiological function of transmembrane and soluble Klotho for Mineral Homeostasis is their role as coreceptors mediating FGF23 actions. In light of these findings, the main pathophysiological consequence of the downregulation of Klotho observed in acute and chronic renal failure may be the induction of renal FGF23 resistance.

  • klotho lacks an fgf23 independent role in Mineral Homeostasis
    Journal of Bone and Mineral Research, 2017
    Co-Authors: Olena Andrukhova, Jessica Bayer, Christiane Schuler, Ute Zeitz, Sathish K Murali, Sibel Ada, Jose M Alvarezpez, Alina Smorodchenko, Reinhold G Erben
    Abstract:

    Fibroblast growth factor-23 (FGF23) is a bone-derived hormone regulating vitamin D hormone production and renal handling of Minerals by signaling through an FGF receptor/αKlotho (Klotho) receptor complex. Whether Klotho has FGF23-independent effects on Mineral Homeostasis is a controversial issue. Here, we aimed to shed more light on this controversy by comparing male and female triple knockout mice with simultaneous deficiency in Fgf23 and Klotho and a nonfunctioning vitamin D receptor (VDR) (Fgf23/Klotho/VDR) with double (Fgf23/VDR, Klotho/VDR, and Fgf23/Klotho) and single Fgf23, Klotho, and VDR mutants. As expected, 4-week-old Fgf23, Klotho, and Fgf23/Klotho knockout mice were hypercalcemic and hyperphosphatemic, whereas VDR, Fgf23/VDR, and Klotho/VDR mice on rescue diet were normocalcemic and normophosphatemic. Serum levels of calcium, phosphate, and sodium did not differ between 4-week-old triple Fgf23/Klotho/VDR and double Fgf23/VDR or Klotho/VDR knockout mice. Notably, 3-month-old Fgf23/Klotho/VDR triple knockout mice were indistinguishable from double Fgf23/VDR and Klotho/VDR compound mutants in terms of serum calcium, serum phosphate, serum sodium, and serum PTH, as well as urinary calcium and sodium excretion. Protein expression analysis revealed increased membrane abundance of sodium-phosphate co-transporter 2a (NaPi-2a), and decreased expression of sodium-chloride co-transporter (NCC) and transient receptor potential cation channel subfamily V member 5 (TRPV5) in Fgf23/Klotho/VDR, Fgf23/VDR, and Klotho/VDR mice, relative to wild-type and VDR mice, but no differences between triple and double knockouts. Further, ex vivo treatment of live kidney slices isolated from wild-type and Klotho/VDR mice with soluble Klotho did not induce changes in intracellular phosphate, calcium or sodium accumulation assessed by two-photon microscopy. In conclusion, our data suggest that the main physiological function of Klotho for Mineral Homeostasis in vivo is its role as co-receptor mediating Fgf23 action. © 2017 American Society for Bone and Mineral Research.

David Goltzman - One of the best experts on this subject based on the ideXlab platform.

  • comparison of active vitamin d compounds and a calcimimetic in Mineral Homeostasis
    Journal of The American Society of Nephrology, 2010
    Co-Authors: Loan Nguyenyamamoto, Isabel Bolivar, Stephen A Strugnell, David Goltzman
    Abstract:

    The differential effects between cinacalcet and active vitamin D compounds on parathyroid function, Mineral metabolism, and skeletal function are incompletely understood. Here, we studied cinacalcet and active vitamin D compounds in mice expressing the null mutation for Cyp27b1, which encodes 25-hydroxyvitamin D-1α-hydroxylase, thereby lacking endogenous 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. Vehicle-treated mice given high dietary calcium had hypocalcemia, hypophosphatemia, and marked secondary hyperparathyroidism. Doxercalciferol and 1,25(OH)(2)D(3) each normalized these parameters and corrected both the abnormal growth plate architecture and the diminished longitudinal bone growth observed in these mice. In contrast, cinacalcet suppressed serum parathyroid hormone (PTH) cyclically and did not correct the skeletal abnormalities and hypocalcemia persisted. Vehicle-treated mice given a "rescue diet" (high calcium and phosphorus, 20% lactose) had normal serum calcium and PTH levels; cinacalcet induced transient hypocalcemia and mild hypercalciuria. The active vitamin D compounds and cinacalcet normalized the increased osteoblast activity observed in mice with secondary hyperparathyroidism; cinacalcet, however, increased the number and activity of osteoclasts. In conclusion, cinacalcet reduces PTH in a cyclical manner, does not eliminate hypocalcemia, and does not correct abnormalities of the growth plate. Doxercalciferol and 1,25(OH)(2)D(3) reduce PTH in a sustained manner, normalize serum calcium, and improve skeletal abnormalities.

  • does calcitriol have actions independent from the vitamin d receptor in maintaining skeletal and Mineral Homeostasis
    Current Opinion in Nephrology and Hypertension, 2005
    Co-Authors: Geoffrey N Hendy, David Goltzman
    Abstract:

    PURPOSE OF REVIEW: Although the active metabolite of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D), is classically appreciated to exert its calcemic and other actions via interaction with the vitamin D receptor, thereby modulating gene transcription, some of its actions cannot be explained in this way when examined in vitro. RECENT FINDINGS: Comparison of mouse models deleted for either the 25-hydroxyvitamin D-1alpha-hydroxylase enzyme (deficient in 1,25(OH)2D) or the vitamin D receptor or both has allowed an assessment of whether 1,25(OH)2D can function in the absence of the vitamin D receptor in vivo. The data indicated that calcium absorption required both the ligand and the receptor as did bone and cartilage remodeling. However, with respect to parathyroid gland function and development of the cartilaginous growth plate, calcium and 1,25(OH)2D acted cooperatively and there was evidence that 1,25(OH)2D could act independently of the vitamin D receptor. SUMMARY: Results from the genetic models are consistent with recent reports that rapid actions of vitamin D metabolites occur in chondrocytes through a membrane receptor distinct from the vitamin D receptor. In addition, in osteoblasts it has been proposed that the vitamin D receptor localized in plasma membrane caveolae signals the rapid effects of the active vitamin D secosterol.

Bo Lonnerdal - One of the best experts on this subject based on the ideXlab platform.

  • molecular regulation of milk trace Mineral Homeostasis
    Molecular Aspects of Medicine, 2005
    Co-Authors: Shannon L Kelleher, Bo Lonnerdal
    Abstract:

    The regulation of milk trace Mineral Homeostasis requires the temporal integration of three main processes, (A) Mineral uptake into the secretory mammary epithelial cell (MEC); followed by (B) Mineral secretion from MEC into the alveoli lumen of the mammary gland for sequestration in milk; and then (C) milk release in response to suckling. Trace Mineral requirements of term infants are generally met by exclusive breast-feeding through about the first 6 months of life and although milk zinc (Zn), iron (Fe), and copper (Cu) concentrations are relatively refractory to maternal trace Mineral status, they normally decline throughout lactation. Recently, Zn-, Fe- and Cu-specific transporters have been identified that regulate trace element uptake and efflux in various cell types; however, there is currently little information available regarding the processes through which the mammary gland regulates milk trace Mineral transport. The homology of trace Mineral transporters between species permits the utilization of rodent models to examine the regulation of mammary gland Mineral transport. Therefore, we have used the lactating rat to determine changes in mammary gland Zn, Fe and Cu transporter expression and localization that occur throughout lactation and in response to maternal trace Mineral deficiency in hope of elucidating some of the changes which occur during mammary gland trace element Homeostasis and also may be occurring in lactating women.

Sundeep Khosla - One of the best experts on this subject based on the ideXlab platform.

  • early effects of androgen deprivation on bone and Mineral Homeostasis in adult men a prospective cohort study
    European Journal of Endocrinology, 2020
    Co-Authors: Rougin Khalil, Na Ri Kim, Leen Antonio, Michael R Laurent, Karel David, Pieter Evenepoel, Anton Eisenhauer, Alexander Heuser, Etienne Cavalier, Sundeep Khosla
    Abstract:

    Objective Long-term androgen deprivation therapy (ADT) negatively influences bone. The short-term effects on bone and Mineral Homeostasis are less known. Therefore, we aimed to investigate the early effects of ADT on calcium/phosphate Homeostasis and bone turnover. Design Prospective cohort study. Methods Eugonadal adult, male sex offenders, who were referred for ADT to the endocrine outpatient clinic, received cyproterone acetate. Changes in blood markers of calcium/phosphate Homeostasis and bone turnover between baseline and first follow-up visit were studied. Results Of 26 screened patients, 17 were included. The median age was 44 (range 20-75) years. The median time interval between baseline and first follow-up was 13 (6-27) weeks. Compared to baseline, an 81% decrease was observed for median total testosterone (to 3.4 nmol/L (0.4-12.2); P < 0.0001) and free testosterone (to 0.06 nmol/L (0.01-0.18); P < 0.0001). Median total estradiol decreased by 71% (to 17.6 pmol/L (4.7-35.6); P < 0.0001). Increased serum calcium (P < 0.0001) and phosphate (P = 0.0016) was observed, paralleled by decreased PTH (P = 0.0156) and 1,25-dihydroxyvitamin D3 (P = 0.0134). The stable calcium isotope ratio (δ44/42Ca) decreased (P = 0.0458), indicating net calcium loss from bone. Bone-specific alkaline phosphatase and osteocalcin decreased (P < 0.0001 and P = 0.0056, respectively), periostin tended to decrease (P = 0.0500), whereas sclerostin increased (P < 0.0001), indicating suppressed bone formation. Serum bone resorption markers (TRAP, CTX) were unaltered. Conclusions In adult men, calcium release from the skeleton occurs early following sex steroid deprivation, reflecting early bone resorption. The increase of sclerostin and reduction of bone formation markers, without changes in resorption markers, suggests a dominant negative effect on bone formation in the acute phase.