The role of parathyroid hormone-related protein (PTHrP) in fetal calcium homeostasis

The role of parathyroid hormone-related protein (PTHrP) in fetal calcium homeostasis and placental calcium transport was examined in mice homozygous for the deletion from the PTHrP gene (placental perfusion of the umbilical circulation at 18 dp was used to measure unidirectional clearance of 45Ca across the placenta in maternofetal (CaKmf) and fetoplacental (CaKfp) directions; CaKfp was 5% of CaKmf for all those genotypes. in life (Tobias & Cooper, 2004). Rabbit polyclonal to ZMAT5 Maximal fetal accretion of calcium occurs over the last third of pregnancy, and in the rat, as in other species, the rise in fetal calcium accretion is usually exponential over this period (Comar, 1956). Net calcium flux to the fetus Dinaciclib cost (Ca1992). Considerable data from a variety of species suggest that Ca2006). Ca2004). In common with other calcium transporting epithelia, calcium transport across the placenta could plausibly involve three main actions (Belkacemi 2005; Atkinson 2006): firstly, diffusion into the trophoblast from maternal plasma down an electrochemical gradient through epithelial Ca2+ channels of the transient receptor potential (TRP) gene family; secondly, Dinaciclib cost transfer across the trophoblast cytoplasm bound to the calcium binding protein calbindin-D9K (Glazier 1992); and, thirdly, active extrusion into the fetal compartment via plasma membrane Ca2+-ATPase (PMCA) localized to the fetal facing basal plasma membrane (Fisher 1987; Borke 1989). Over the last third of gestation, gene and protein expression for calbindin-D9K increases markedly in both mouse and rat placenta (Mathieu 1989; Glazier 1992; Hamilton 2000; An 2004) whereas rat placental Ca2+-ATPase expression shows only a 2- to 3-fold increase (Glazier 1992). This increase in rat placental calbindin-D9K expression is associated with a concomitant, stoichiometric increase in unidirectional maternofetal 45Ca clearance over this period leading to the speculation that calbindin-D9K may be rate limiting for placental calcium transport in this species (Glazier 1992). One of the fetal factors implicated in the regulation of placental calcium transport is usually parathyroid hormone-related protein (PTHrP), which is usually produced by the placenta as well as by other fetal tissues (Tobias & Cooper, 2004). Although PTHrP was initially discovered as the humoral factor responsible for hypercalcaemia of malignancy, it is now known to have broad expression in a variety of fetal and adult tissues (examined Dinaciclib cost in Philbrick 1996). The versatility of PTHrP in performing multiple, yet unique, biological effects through endocrine, autocrine, paracrine and intracrine activities arises from alternate splicing of the PTHrP gene, giving rise to three initial translation products which then undergo post-translational processing to generate N-terminal, mid-region and C-terminal mature peptide fragments. Consistent with this concept, calcium transfer into blood used to perfuse the fetal blood circulation of the placenta in thyroparathyroidectomised fetal lambs was increased by the addition of partially purified hPTHrP or recombinant PTHrP(1C84), PTHrP(1C108) and PTHrP(1C141) but not by synthetic PTHrP(1C34) (Abbas 1989). This activation was quick (within 1 h) and was also conferred by hPTHrP(67C86 amide) and hPTHrP(75C86 amide) fragments (Care 1990) suggesting that activity resides in the PTHrP(75C86) peptide series which the N-terminus isn’t involved. In comparison, infusion of hPTHrP(1C34) or hPTHrP(75C86 amide) in to the fetoplacental flow of unchanged rat fetuses acquired no influence on the placental transportation of calcium mineral (Shaw 1991). The option of fetal mice homozygous for deletion from the gene (PTHrP?/? null; NL) (Karaplis 1994) provides allowed closer study of the result of fetal PTHrP on placental calcium mineral transportation. NL fetuses display abnormalities of endochondral bone tissue advancement with accelerated Dinaciclib cost endochondral ossification, however, despite wide PTHrP tissue appearance in PTHrP+/+ wild-type (WT) conceptuses, no gross morphological abnormalities had been apparent in various other tissue from NL fetuses (Karaplis 1994). In NL fetuses, fetal bloodstream ionized Ca2+ focus is significantly decreased leading Dinaciclib cost to the abolition from the fetomaternal Ca2+ gradient (Kovacs 1996; Tucci 1996). The proportion of maternofetal transfer of 45Ca normalized compared to that of 51Cr-EDTA (utilized being a marker of diffusional permeability) was.

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