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Abstract
We employed a genetic approach to determine whether deficiency of 1,25-dihydroxyvitamin D (1,25(OH)2D) and deficiency of the vitamin D receptor (VDR) produce the same alterations in skeletal and calcium homeostasis and whether calcium can subserve the skeletal functions of 1,25(OH)2D and the VDR. Mice with targeted deletion of the 25-hydroxyvitamin D 1alpha-hydroxylase (1alpha(OH)ase-/-) gene, the VDR gene, and both genes were exposed to 1) a high calcium intake, which maintained fertility but left mice hypocalcemic; 2) this intake plus three times weekly injections of 1,25(OH)2D3, which normalized calcium in the 1alpha(OH)ase-/- mice only; or 3) a "rescue" diet, which normalized calcium in all mutants. These regimens induced different phenotypic changes, thereby disclosing selective modulation by calcium and the vitamin D system. Parathyroid gland size and the development of the cartilaginous growth plate were each regulated by calcium and by 1,25(OH)2D3 but independent of the VDR. Parathyroid hormone secretion and mineralization of bone reflected ambient calcium levels rather than the 1,25(OH)2D/VDR system. In contrast, increased calcium absorption and optimal osteoblastogenesis and osteoclastogenesis were modulated by the 1,25(OH)2D/VDR system. These studies indicate that the calcium ion and the 1,25(OH)2D/VDR system exert discrete effects on skeletal and calcium homeostasis, which may occur coordinately or independently.
Highlights
Vitamin D plays a major role in modulating calcium and skeletal homeostasis and exerts a significant influence on the growth and differentiation of a variety of tissues (1–3)
We employed a genetic approach to determine whether deficiency of 1,25-dihydroxyvitamin D (1,25(OH)2D) and deficiency of the vitamin D receptor (VDR) produce the same alterations in skeletal and calcium homeostasis and whether calcium can subserve the skeletal functions of 1,25(OH)2D and the VDR
Expression of 1␣(OH)ase and 24(OH)ase Genes—The 1␣(OH)ase gene was expressed at higher levels in the VDRϪ/Ϫ mice than in wild-type mice when animals received a high calcium intake (Fig. 1b, left panel); this was not reduced by administering exogenous 1,25(OH)2D3 to these animals (Fig. 1b, right panel) but was reduced by eliminating hypocalcemia with the rescue diet (Fig. 1b, middle panel)
Summary
1,25(OH)2D, 1,25-dihydroxyvitamin D; Cbfa I, core binding factor a I; 1␣(OH)ase, 25-hydroxyvitamin D-1␣hydroxylase; PTH, parathyroid hormone; 24(OH)ase, 25-hydroxyvitamin D-24-hydroxylase; VDR, vitamin D receptor; RANKL, receptor activator of nuclear factor B ligand; RT, reverse transcriptase; ALP, alkaline phosphatase; TRAP, tartrate-resistant acid phosphatase; WT, wild-type; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. If the major role of the VDR in skeletal function is to increase extracellular fluid calcium by increasing intestinal absorption, as has been postulated (26), the three mutant animals should exhibit similar skeletal phenotypic changes as the serum calcium is altered. To test these hypotheses, we mated heterozygous animals with deletion of the 1␣(OH)ase and the VDR and compared siblings that were homozygous for deletion of the genes encoding 1␣(OH)ase, VDR, and both genes. The use of the double mutants permitted us to explore whether the elevated endogenous 1,25(OH)2D levels seen in VDRϪ/Ϫ mice might play a role in defining the phenotypes observed We exposed these mutants to environmental conditions that would alter concentrations of the calcium ion or of the 1,25(OH)2D3 ligand. The results demonstrate significant phenotypic differences that suggest discrete roles for the calcium ion and components of the 1,25(OH)2D/VDR endocrine system in modulating mineral and skeletal homeostasis
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