The direct role of vitamin D on bone homeostasis.
Vitamin D requires two metabolic conversions, 25-hydroxylation in the liver and 1alpha-hydroxylation in the kidney, before its hormonal form, 1,25-dihydroxyvitamin D [1,25-(OH)2D], can bind to the vitamin D receptor (VDR) to modulate gene transcription and regulate mineral ion homeostasis. The receptor and metabolic enzymes are expressed in many tissues, however, which has long suggested that the vitamin D hormone could act in an autocrine, paracrine, or intracrine fashion to affect the biology of non-classical target tissues. Strong support for this model has been obtained for Toll-like receptor-mediated innate immunity in macrophages, for example. The classical view is that vitamin D exerts its effects on bone indirectly via control of calcium and phosphate homeostasis, despite expression of cyp27b1, the 25-hydroxyvitamin D-1alpha-hydroxylase, and the VDR in osteoblasts and chondrocytes. Recent molecular genetic studies have revealed direct, but non-essential roles for 1,25-(OH)2D in growth plate chondrocytes. Specific inactivation of the VDR in collagen type II-expressing chondrocytes leads to reduced RANKL expression and delayed osteoclastogenesis, which causes a transient increase in bone volume at the primary spongiosa. Chondrocyte-specific VDR-ablated mice also show reduced circulating levels of FGF23 and thus elevated serum phosphate concentrations. The mechanisms remain to be completely determined but appear to involve a 1,25-(OH)2D-induced secreted factor from chondrocytes that affects FGF23 production by neighboring osteoblasts. The phenotype of additional mutant mice models, including chondrocyte-specific inactivation or overexpression of cyp27b1, is being analyzed to provide further support for these results that show autocrine and paracrine roles for 1,25-(OH)2D during endochondral bone development.
St-Arnaud
René
R
Genetics Unit, Shriners Hospital for Children, 1529 Cedar Avenue, Montreal, QC., Canada.
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism; D000818:Animals; D001842:Bone and Bones / Q000502:physiology*; D002118:Calcium / Q000502:physiology; D002454:Cell Differentiation; D019902:Chondrocytes / Q000166:cytology / Q000502:physiology; D000089703:Fibroblast Growth Factor-23; D006706:Homeostasis; D006801:Humans; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D010012:Osteogenesis; D010710:Phosphates / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015398:Signal Transduction; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000502:physiology
C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010710:Phosphates; D053245:RANK Ligand; D018167:Receptors, Calcitriol; D014807:Vitamin D; D000089703:Fibroblast Growth Factor-23; C104450:25-hydroxyvitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002118:Calcium