title: Inferences from genetically modified mouse models on the skeletal actions of vitamin D.
abstract: Vitamin D has pleiotropic extra-skeletal effects which have been noted in mouse models of deletion of either the 25-hydroxy vitamin D 1α-hydroxylase enzyme, cyp27b1 (1OHase(-/-) mice) or of the vitamin D receptor (Vdr(-/-) mice); these may be preventable or reversible by either restoring normal signaling of the 1,25(OH)2D/VDR system, or in some cases by restoring normal mineral homeostasis. However, effects on skeletal and mineral homeostasis are clearly the major phenotype observed in humans with loss-of-function mutations in either CYP27B1 or VDR. In mouse phenocopies of these human disorders, correction of hypocalcemia and hypophosphatemia reduce elevated circulating parathyroid hormone concentrations and normalize impaired bone mineralization, but restoration of normal 1,25(OH)2D/VDR signaling may be required for optimal bone formation. Induction of high endogenous 1,25(OH)2D concentrations in genetically modified mouse models may cause increased bone resorption and decreased mineralization. Transgenic Vdr overexpression and conditional Vdr deletion in cells of the osteoblastic lineage have also provided insights into the stages of osteoblast differentiation which may mediate these actions. These anabolic and catabolic effects of the 1,25(OH)2D system on bone may therefore be a function of both the ambient concentration of circulating 1,25(OH)2D and the stage of differentiation of the osteoblast. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.
authors.affiliation: Calcium Research Laboratory, Departments of Medicine and Physiology, McGill University Health Centre, Montreal, Quebec H3A 1A1, Canada. Electronic address: david.goltzman@mcgill.ca.
authors.forename: D
authors.initials: D
authors.lastname: Goltzman
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000502:physiology*; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018167:Receptors, Calcitriol / Q000502:physiology*
chemical_list: D018167:Receptors, Calcitriol; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase
keywords: 1,25-Dihydroxyvitamin D; 1α-Hydroxylase; Bone; Cyp27b1; Extra-skeletal effects; Genetic mouse models; Osteoblast; Osteoclasts; Osteocytes; Targeted deletion; Vitamin D; Vitamin D receptor