• Demay Marie B

Annals of the New York Academy of Sciences

• Publish Date: Apr 2006
• ISSN: 0077-8923
• Volume: 1068
• Issue:
• Pages: 204-13
• Medium: Print
• Language: English
• Citation (JAMA): Demay Marie B, et al. Mechanism of Vitamin D Receptor Action.. Ann. N. Y. Acad. Sci. Apr 2006;1068:204-13

Abstract

Studies in humans and in animal models have demonstrated that the receptor-dependent actions of 1,25-dihydroxyvitamin D are required for normal skeletal growth and maturation. Investigations were undertaken to address which consequences of vitamin D receptor deficiency are a direct result of impaired receptor-dependent hormone actions versus being due to metabolic changes. Vitamin D receptor (VDR) knockout mice were therefore generated. Investigations were performed in mice with abnormal mineral ion homeostasis, as well as in mice in which the development of abnormal mineral ion homeostasis was prevented by dietary means. VDR null mice had hypocalcemia, hyperparathyroidism, and hypophosphatemia in the first month of life. Rickets and osteomalacia are observed as well. Institution of a high-calcium, high-phosphorus, lactose-supplemented diet by the third week of life prevents abnormalities in mineral ion homeostasis. The bones of the VDR null mice with normal mineral ion homeostasis are indistinguishable from those of their wild-type littermates. The rachitic changes in the growth plates are also prevented by maintenance of normal mineral ion homeostasis. Investigations into the pathophysiological basis for the growth plate abnormalities in the VDR null mice with abnormal mineral ion homeostasis demonstrated that impaired apoptosis of hypertrophic chondrocytes due to hypophosphatemia was the cause of rachitic changes. Studies investigating the cause of the alopecia demonstrate novel ligand-independent VDR actions in the keratinocyte. The skeletal effects of VDR ablation are therefore indirect and reflect absence of ligand-dependent receptor actions in the intestine. In contrast, the cutaneous phenotype of VDR ablation is a direct consequence of absence of ligand-independent VDR actions in epidermal keratinocytes.

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