A line of mice deficient in vitamin D binding protein (DBP) was generated by targeted mutagenesis to establish a model for analysis of DBP's biological 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 otherwise normal. When maintained on vitamin D–deficient diets for a brief period, the DBP–/–, but not DBP+/+, mice developed secondary hyperparathyroidism and the accompanying bone changes associated with vitamin D deficiency. DBP markedly prolonged the serum half-life of 25(OH)D and less dramatically prolonged the half-life of vitamin D by slowing its hepatic uptake and increasing the efficiency of its conversion to 25(OH)D in the liver. After an overload of vitamin D, DBP–/– mice were unexpectedly less susceptible to hypercalcemia and its toxic effects. Peak steady-state mRNA levels of the vitamin D–dependent calbindin-D9K gene were induced by 1,25(OH)2D more rapidly 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 bioavailability, activation, and end-organ responsiveness. These properties may have evolved to stabilize and maintain serum levels of vitamin D in environments with variable vitamin D availability.
Fayez F. Safadi, Paul Thornton, Holly Magiera, Bruce W. Hollis, Michael Gentile, John G. Haddad, Stephen A. Liebhaber, Nancy E. Cooke
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