Effects of vitamin D receptor inactivation on the expression of calbindinsand calcium metabolism

Hypocalcemia, rickets, and osteomalacia are major phenotypic abnormalities in vitamin D receptor (VDR)-null mice. In an attempt to understand the abno rmal regulation of calcium metabolism in these animals, we examined the exp ression of calbindins (CaBP) as well as calcium handling in the intestine a nd kidney of VDR null mice. In adult VDR-null mice, intestinal and renal Ca BP-D9k expression was reduced by 50 and 90%, respectively, at both the mRNA and protein levels compared with wild-type littermates, whereas renal CaBP -D28k expression was not significantly changed. Intestinal calcium absorpti on was measured by the rate of Ca-45 disappearance from the intestine after an oral dose of the isotope. Ca-45 absorption was similar in VDR-null and wildtype mice, but the amount of Ca-45 accumulated in the serum and bone wa s 3-4 times higher in wild-type mice than in VDR-null mice. Despite the hyp ocalcemia, the urinary excretion of calcium in VDR-null mice was not differ ent from that in wild-type mice. Moreover, 1 wk of a high-calcium diet trea tment that normalized the serum ionized calcium level of VDR-null mice incr eased the urinary calcium level of these mutant mice to twofold higher than that of wild-type mice on the same diet, suggesting impaired renal calcium conservation in VDR-null mice. These data demonstrate that renal CaBP-D9k, but not CaBP-D28k, is highly regulated by the VDR-mediated action of 1,25- dihydroxyvitamin D-3. Furthermore, the results also suggest that impaired c alcium conservation in the kidney may be the most important factor contribu ting to the development of hypocalcemia in VDR-null mice, and CaBP-D9k may be an important mediator of calcium reabsorption in the kidney.