Does calcitriol have actions independent from the vitamin D receptor in maintaining skeletal and mineral homeostasis?

Abstract

Although the active metabolite of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D), is classically appreciated to exert its calcemic and other actions via interaction with the vitamin D receptor, thereby modulating gene transcription, some of its actions cannot be explained in this way when examined in vitro. Comparison of mouse models deleted for either the 25-hydroxyvitamin D-1alpha-hydroxylase enzyme (deficient in 1,25(OH)2D) or the vitamin D receptor or both has allowed an assessment of whether 1,25(OH)2D can function in the absence of the vitamin D receptor in vivo. The data indicated that calcium absorption required both the ligand and the receptor as did bone and cartilage remodeling. However, with respect to parathyroid gland function and development of the cartilaginous growth plate, calcium and 1,25(OH)2D acted cooperatively and there was evidence that 1,25(OH)2D could act independently of the vitamin D receptor. Results from the genetic models are consistent with recent reports that rapid actions of vitamin D metabolites occur in chondrocytes through a membrane receptor distinct from the vitamin D receptor. In addition, in osteoblasts it has been proposed that the vitamin D receptor localized in plasma membrane caveolae signals the rapid effects of the active vitamin D secosterol.