HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/F671    most recent 00156.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Segawa, H. Articles by Miyamoto, K.-i. PubMed PubMed Citation Articles by Segawa, H. Articles by Miyamoto, K.-i.

Npt2a and Npt2c in mice play distinct and synergistic roles in inorganic phosphate metabolism and skeletal development

¹Department of Molecular Nutrition, Institution of Health Biosciences, University of Tokushima Graduate School, Tokushima; ²Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima; ³Center for Transdisciplinary Research, Niigata University, Niigata, Japan; and ⁴Departments of Developmental Biology of Hard Tissue, Division of Oral Health Science, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan

Submitted 14 March 2009 ; accepted in final form 18 June 2009

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessively inherited disorder, characterized by hypophosphatemia, short stature, rickets and/or osteomalacia, and secondary absorptive hypercalciuria. HHRH is caused by a defect in the sodium-dependent phosphate transporter (NaPi-IIc/Npt2c/NPT2c), which was thought to have only a minor role in renal phosphate (P_i) reabsorption in adult mice. In fact, mice that are null for Npt2c (Npt2c^–/–) show no evidence for renal phosphate wasting when maintained on a diet with a normal phosphate content. To obtain insights and the relative importance of Npt2a and Npt2c, we now studied Npt2a^–/–Npt2c^+/+, Npt2a^+/–Npt2c^–/–, and Npt2a^–/–Npt2c^–/– double-knockout (DKO). DKO mice exhibited severe hypophosphatemia, hypercalciuria, and rickets. These findings are different from those in Npt2a KO mice that show only a mild phosphate and bone phenotype that improve over time and from the findings in Npt2c KO mice that show no apparent abnormality in the regulation of phosphate homeostasis. Because of the nonreddundant roles of Npt2a and Npt2c, DKO animals showed a more pronounced reduction in P_i transport activity in the brush-border membrane of renal tubular cells than that in the mice with the single-gene ablations. A high-P_i diet after weaning rescued plasma phosphate levels and the bone phenotype in DKO mice. Our findings thus showed in mice that Npt2a and Npt2c have independent roles in the regulation of plasma P_i and bone mineralization.

hereditary hypophosphatemic rickets; bone mineralization