Type IIc sodium-dependent phosphate transporter regulates calcium metabolism

Area of Science:

• Nephrology
• Endocrinology
• Bone Biology

Background:

• Primary renal inorganic phosphate (Pi) wasting causes hypophosphatemia and skeletal mineralization defects.
• Mutations in the gene for the type IIc sodium-dependent phosphate transporter (Npt2c) cause hereditary hypophosphatemic rickets with hypercalciuria in humans.
• The direct causal link between Pi wasting and bone disorders remains unclear.

Purpose of the Study:

• To define the role of Npt2c in phosphate homeostasis and bone abnormalities using Npt2c-null mice.
• To investigate the contribution of Npt2c to calcium (Ca) metabolism and vitamin D regulation.

Main Methods:

• Generation of Npt2c-null (Npt2c(-/-)) mice.
• Analysis of plasma and urinary biochemistry, including phosphate, calcium, and vitamin D levels.
• Measurement of gene expression for vitamin D hydroxylases and fibroblast growth factor 23 (FGF23).
• Assessment of renal sodium-dependent Pi co-transport.

Main Results:

• Npt2c(-/-) mice exhibited hypercalcemia, hypercalciuria, and elevated plasma 1,25-dihydroxyvitamin D(3) but no hypophosphatemia or bone abnormalities.
• Reduced expression of renal 25-hydroxyvitamin D-24-hydroxylase mRNA was observed, suggesting decreased vitamin D catabolism.
• Enhanced intestinal Ca absorption contributed to hypercalcemia and hypercalciuria.
• Plasma FGF23 levels were significantly decreased in Npt2c(-/-) mice.
• Renal sodium-dependent Pi co-transport was not different across genotypes.

Conclusions:

• Npt2c is not essential for preventing hypophosphatemia or rickets.
• Npt2c plays a role in maintaining normal calcium metabolism, partly by modulating the vitamin D/FGF23 axis.
• These findings suggest Npt2c's function extends beyond phosphate transport in regulating mineral homeostasis.