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

• Published in: Biochemical and biophysical research communications Vol. 467; no. 1; pp. 152 - 156
• Main Authors: Ryan, Zachary C., Craig, Theodore A., Filoteo, Adelaida G., Westendorf, Jennifer J., Cartwright, Elizabeth J., Neyses, Ludwig, Strehler, Emanuel E., Kumar, Rajiv
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.11.2015
• Subjects: 1α,25-dihydroxyvitamin D3; Animals; Atp2b1; Bone density; Bone Density - drug effects; Bone Density - genetics; Bone Density - physiology; Bone Density Conservation Agents - pharmacology; Calcification, Physiologic - drug effects; Calcification, Physiologic - genetics; Calcification, Physiologic - physiology; Calcitriol - pharmacology; Calcium transport; Female; Gene Knockout Techniques - methods; Intestinal Absorption - drug effects; Intestinal Absorption - genetics; Intestinal Absorption - physiology; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Intestine; Male; Mice; Mice, Knockout; Plasma membrane calcium pump; Plasma Membrane Calcium-Transporting ATPases - deficiency; Plasma Membrane Calcium-Transporting ATPases - genetics; Pmca1; 1α,25-dihydroxyvitamin D3; Atp2b1; Intestine; Bone density; Calcium transport; Plasma membrane calcium pump; Pmca1; 1α,25-dihydroxyvitamin D
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2015.09.087

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 (Pmca1fl/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 (Pmca1EKO mice). Pmca1EKO 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, Pmca1EKO 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 Pmca1EKO mice compared to Wt mice but the changes were not statistically significant. The urinary phosphorus/creatinine ratio was increased in Pmca1EKO 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 Pmca1EKO 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. •The Pmca1 was deleted in the intestine to examine its role in Ca homeostasis in vivo.•Mice with intestinal Pmca1 deletion are born with reduced frequency and are stunted at birth.•At two months of age mice with intestinal Pmca1 deletion have reduced bone mineral density.•1α,25(OH)2D3-induced Ca transport is impaired in mice with intestinal Pmca1 deletion.