Osteopathy and resistance to vitamin D toxicity in mice null for vitamin Dbinding protein

A line of mice deficient in vitamin D binding protein (DBP) was generated b y targeted mutagenesis to establish a model for analysis of DBP's biologica l functions in vitamin D metabolism and action. On vitamin D-replete diets, DBP-/- mice had low levels of total serum vitamin D metabolites but were o therwise normal. When maintained on vitamin D-deficient diets for a brief p eriod, the DBP-/-, but not DBP+/+, mice developed secondary hyperparathyroi dism and the accompanying bone changes associated with vitamin D deficiency . DBP markedly prolonged the serum half-life of 25(OH)D and less dramatical ly prolonged the half-life of vitamin D by slowing its hepatic uptake and i ncreasing the efficiency of its conversion to 25(OH)D in the liver. After a n overload of vitamin D, DBP-/- mice were unexpectedly less susceptible to hypercalcemia and its toxic effects. Peak steady-state mRNA levels of the v itamin D-dependent calbindin-D-9K gene were induced by 1,25(OH)(2)D more ra pidly in the DBP-/- mice. Thus, the role of DBP is to maintain stable serum stores of vitamin D metabolites and modulate the rates of its bioavailabil ity, activation, and end-organ responsiveness. These properties may have ev olved to stabilize and maintain serum levels of vitamin D in environments w ith variable vitamin D availability.