Submitted on March 16, 2009
Revised on June 8, 2009
Accepted on June 18, 2009
Npt2a and Npt2c in mice play distinct and synergistic roles in inorganic phosphate metabolism and skeletal development
Hiroko Segawa1, Akemi Onitsuka1, Junya Furutani, Ichiro Kaneko1, Fumito Aranami, Natsuki Matsumoto1, Yuka Tomoe, Masashi Kuwahata1, Mikiko Ito2, Mitsuru Matsumoto3, Minqi Li4, Norio Amizuka5, and Ken-ichi Miyamoto6*
1 Institution of Health Biosciences, The University of Tokushima Graduate School, Tokushima
2 The university of Tokushima Graduate School
3 Institute for Enzyme Research, University of Tokushima
4 Niigata University
5 Niigata
6 Tokushima University
* To whom correspondence should be addressed. E-mail: miyamoto{at}nutr.med.tokushima-u.ac.jp.
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 (Pi) 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 non-reddundant roles of Npt2a and Npt2c, DKO animals showed a more pronounced reduction in Pi transport activity in the brush border membrane of renal tubular cells than that in the mice with the single gene ablations. A high Pi 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 Pi and bone mineralization.
