title: Deletion of the intestinal plasma membrane calcium pump, isoform 1, Atp2b1, in mice is associated with decreased bone mineral density and impaired responsiveness to 1, 25-dihydroxyvitamin D3.
abstract: The physiological importance of the intestinal plasma membrane calcium pump, isoform 1, (Pmca1, Atp2b1), in calcium absorption and homeostasis has not been previously demonstrated in vivo. Since global germ-line deletion of the Pmca1 in mice is associated with embryonic lethality, we selectively deleted the Pmca1 in intestinal absorptive cells. Mice with loxP sites flanking exon 2 of the Pmca1 gene (Pmca1(fl/fl)) were crossed with mice expressing Cre recombinase in the intestine under control of the villin promoter to give mice in which the Pmca1 had been deleted in the intestine (Pmca1(EKO) mice). Pmca1(EKO) mice were born at a reduced frequency and were small at the time of birth when compared to wild-type (Wt) littermates. At two months of age, Pmca1(EKO) mice fed a 0.81% calcium, 0.34% phosphorus, normal vitamin D diet had reduced whole body bone mineral density (P < 0.037), and reduced femoral bone mineral density (P < 0.015). There was a trend towards lower serum calcium and higher serum parathyroid hormone (PTH) and 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) concentrations in Pmca1(EKO) mice compared to Wt mice but the changes were not statistically significant. The urinary phosphorus/creatinine ratio was increased in Pmca1(EKO) mice (P < 0.004). Following the administration of 200 ng of 1α,25(OH)2D3 intraperitoneally to Wt mice, active intestinal calcium transport increased ∼2-fold, whereas Pmca1(EKO) mice administered an equal amount of 1α,25(OH)2D3 failed to show an increase in active calcium transport. Deletion of the Pmca1 in the intestine is associated with reduced growth and bone mineralization, and a failure to up-regulate calcium absorption in response to 1α,25(OH)2D3.
authors.affiliation: Nephrology Research, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Ryan
authors.affiliation: Nephrology Research, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Craig
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: Adelaida G
authors.initials: AG
authors.lastname: Filoteo
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA; Department of Orthopedic Surgery, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Westendorf
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Cartwright
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, Manchester, M13 9PT, UK; University of Luxembourg, L-4365, Esch-sur-Alzette, Luxembourg.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Neyses
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA. Electronic address: strehler.emanuel@mayo.edu.
authors.forename: Emanuel E
authors.initials: EE
authors.lastname: Strehler
authors.affiliation: Nephrology Research, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA. Electronic address: rkumar@mayo.edu.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D002113:Calcification, Physiologic / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002117:Calcitriol / Q000494:pharmacology*; D005260:Female; D055786:Gene Knockout Techniques / Q000379:methods; D007408:Intestinal Absorption / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000172:deficiency* / Q000235:genetics
chemical_list: D050071:Bone Density Conservation Agents; D053499:Plasma Membrane Calcium-Transporting ATPases; C506954:Atp2b1 protein, mouse; D002117:Calcitriol
keywords: 1α,25-dihydroxyvitamin D(3); Atp2b1; Bone density; Calcium transport; Intestine; Plasma membrane calcium pump; Pmca1