title: Type IIc sodium-dependent phosphate transporter regulates calcium metabolism.
abstract: Primary renal inorganic phosphate (Pi) wasting leads to hypophosphatemia, which is associated with skeletal mineralization defects. In humans, mutations in the gene encoding the type IIc sodium-dependent phosphate transporter lead to hereditary hypophophatemic rickets with hypercalciuria, but whether Pi wasting directly causes the bone disorder is unknown. Here, we generated Npt2c-null mice to define the contribution of Npt2c to Pi homeostasis and to bone abnormalities. Homozygous mutants (Npt2c(-/-)) exhibited hypercalcemia, hypercalciuria, and elevated plasma 1,25-dihydroxyvitamin D(3) levels, but they did not develop hypophosphatemia, hyperphosphaturia, renal calcification, rickets, or osteomalacia. The increased levels of 1,25-dihydroxyvitamin D(3) in Npt2c(-/-) mice compared with age-matched Npt2c(+/+) mice may be the result of reduced catabolism, because we observed significantly reduced expression of renal 25-hydroxyvitamin D-24-hydroxylase mRNA but no change in 1alpha-hydroxylase mRNA levels. Enhanced intestinal absorption of calcium (Ca) contributed to the hypercalcemia and increased urinary Ca excretion. Furthermore, plasma levels of the phosphaturic protein fibroblast growth factor 23 were significantly decreased in Npt2c(-/-) mice. Sodium-dependent Pi co-transport at the renal brush border membrane, however, was not different among Npt2c(+/+), Npt2c(+/-), and Npt2c(-/-) mice. In summary, these data suggest that Npt2c maintains normal Ca metabolism, in part by modulating the vitamin D/fibroblast growth factor 23 axis.
authors.affiliation: Department of Molecular Nutrition, Institution of Health Bioscience, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Segawa
authors.forename: Akemi
authors.initials: A
authors.lastname: Onitsuka
authors.forename: Masashi
authors.initials: M
authors.lastname: Kuwahata
authors.forename: Etsuyo
authors.initials: E
authors.lastname: Hanabusa
authors.forename: Junya
authors.initials: J
authors.lastname: Furutani
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kaneko
authors.forename: Yuka
authors.initials: Y
authors.lastname: Tomoe
authors.forename: Fumito
authors.initials: F
authors.lastname: Aranami
authors.forename: Natsuki
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Mikiko
authors.initials: M
authors.lastname: Ito
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Minqi
authors.initials: M
authors.lastname: Li
authors.forename: Norio
authors.initials: N
authors.lastname: Amizuka
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Miyamoto
mesh_terms: D000818:Animals; D001692:Biological Transport; D001842:Bone and Bones / Q000737:chemistry / Q000473:pathology; D064026:Calbindins; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics; D005215:Fasting / Q000378:metabolism; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010710:Phosphates / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D064030:S100 Calcium Binding Protein G / Q000235:genetics; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc / Q000235:genetics / Q000502:physiology*; D050916:TRPV Cation Channels / Q000235:genetics
chemical_list: D064026:Calbindins; D015220:Calcium Channels; D010710:Phosphates; D012333:RNA, Messenger; D064030:S100 Calcium Binding Protein G; C493563:Slc34a3 protein, mouse; D050615:Sodium-Phosphate Cotransporter Proteins, Type IIc; D050916:TRPV Cation Channels; C492240:Trpv5 protein, mouse; C446923:Trpv6 protein, mouse; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D002118:Calcium