Physiological insights from the vitamin D receptor knockout mouse

Abstract

Identification of vitamin D as a potent antirachitic factor almost a century ago prompted investigations aimed at addressing its mechanism of action and key target tissues. Studies in vitamin D deficiency models and in kindreds with impaired hormone activation and function were critical in identifying key steps in the vitamin D signaling pathway. Studies in humans with vitamin D receptor (VDR) mutations provided a tremendous amount of information regarding the role of this receptor in calcium and skeletal homeostasis. The availability of mouse models of VDR ablation provided an important tool for detailed molecular analyses of the pathophysiologic basis for the skeletal, parathyroid and cutaneous phenotypes observed in mice and humans with impaired VDR function. These investigations revealed that a critical action of the liganded receptor is the promotion of intestinal calcium absorption. Bypassing this defect by dietary or transgenic rescue prevents the severe skeletal phenotype of the VDR ablated mice, as well as the development of hyperparathyroidism. In contrast, intestine specific ablation of the receptor results in marked skeletal pathology. Like their human counterparts, VDR knockout mice develop alopecia. Studies in these mice demonstrated that the actions of the VDR required for cyclical regeneration of the hair follicle and prevention of alopecia were shown independent of 1,25-dihydroxyvitamin D demonstrating that the unliganded receptor has an important role in the cutaneous homeostasis.

Fig. 1

Skeletal phenotype of VDR null mice at 35 days of age. Radiographs of the tibia and fibula of Wildtype (A) and VDR null mice (B) are shown. Arrow heads point to the cortical bone, which is undermineralized, thus thinner in the VDR null mouse. Arrow points to the expanded, radiolucent growth plate, classic for rickets. Von kossa staining demonstrates a decrease in mineral in the cortical and trabecular bone of the VDR null mouse (D), relative to its wildtype littermate, as well as expansion of the growth plate. Modified from [2]. Copyright 1997, National Academy of Sciences, U.S.A.

Fig. 2

Alopecia and growth retardation in Vitamin D receptor null mice. Appearance of wildtype (left), heterozygous (middle) and homozygous (right) vitamin D receptor knockout littermates at 3.5 months of age. Reproduced from [2]. Copyright 1997, National Academy of Sciences, U.S.A.

Fig. 3

Skin phenotype of VDR-null mice. Skin from 8-month-old VDR-null mice (B) demonstrates lipid-laden dermal cysts (arrowheads) and an increase in sebaceous activity (arrows), relative to that seen in wildtype mice (A). Sections were stained for lipid with oil-red-O and counterstained with hematoxylin. Modified from [42]. Copyright 2007, National Academy of Sciences, U.S.A.