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Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein
Fayez F. Safadi, … , Stephen A. Liebhaber, Nancy E. Cooke
Fayez F. Safadi, … , Stephen A. Liebhaber, Nancy E. Cooke
Published January 15, 1999
Citation Information: J Clin Invest. 1999;103(2):239-251. https://doi.org/10.1172/JCI5244.
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Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein

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Abstract

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.

Authors

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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Figure 7

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Relative resistance to vitamin D3 toxicity demonstrated by DBP–/– mice. ...
Relative resistance to vitamin D3 toxicity demonstrated by DBP–/– mice. DBP+/+ and DBP–/– mice were injected with toxic doses of vitamin D or with vehicle alone. (a) Serum calcium levels were determined 7 days after injection, and results are expressed as a percentage of the serum calcium in the vehicle-injected control groups. The differences were significant in both comparisons: DBP+/+ group (P < 0.001) and DBP–/– group (P < 0.01) compared with vehicle (not shown), and the calcium increase in the DBP+/+ group compared with the DBP–/– group (P < 0.05, shown). Seven days after injection, kidney sections were fixed and stained with von Kossa to detect calcium deposits. Representative kidney sections from DBP+/+ mice injected with vehicle (b) or vitamin D (c), and DBP–/– mice injected with vehicle (d) or vitamin D (e) are shown (×10). The arrows (c and e) point to calcium deposits in the renal cortex, and these regions are shown in the insets (×20).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 5 patents
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