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

J Clin Invest. 1999 Jan;103(2):239-51. doi: 10.1172/JCI5244.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bone Diseases / genetics*
  • Bone Diseases / pathology
  • Calbindins
  • Calcifediol / pharmacokinetics
  • Calcification, Physiologic / genetics
  • Gene Targeting / methods
  • Hypercalcemia / metabolism
  • Hyperparathyroidism, Secondary / genetics
  • Kidney / pathology
  • Liver / metabolism
  • Mice
  • Mice, Knockout
  • Parathyroid Hormone / blood
  • RNA, Messenger / genetics
  • S100 Calcium Binding Protein G / genetics
  • Transcriptional Activation / genetics
  • Vitamin D / analogs & derivatives
  • Vitamin D / blood
  • Vitamin D / metabolism
  • Vitamin D Deficiency / metabolism
  • Vitamin D-Binding Protein / genetics*

Substances

  • Calbindins
  • Parathyroid Hormone
  • RNA, Messenger
  • S100 Calcium Binding Protein G
  • S100g protein, mouse
  • Vitamin D-Binding Protein
  • Vitamin D
  • 1,25-dihydroxyvitamin D
  • 25-hydroxyvitamin D
  • Calcifediol