Vitamin D metabolites modulate osteoblast activity by Ca+2 influx-independent genomic and Ca+2 influx-dependent nongenomic pathways.
Previous studies have shown that 1,25(OH)2D3 activates multiple signaling pathways in osteoblasts, including rapid nongenomic and long-term genomic pathways. Genomic pathways are mediated by the vitamin D receptor (VDR), a member of the steroid receptor superfamily, and involve transcriptional regulation of target genes. Nongenomic pathways involve lipid turnover, activation of Ca+2 channels and elevation of intracellular Ca+2, all of which occur within seconds after addition of seco-steroid. The interaction of other physiological metabolites of vitamin D, such as 24,25(OH)2D3, with target cells such as osteoblasts is much less clear. We have used a combination of electrophysiological, biochemical, molecular and ion tracer studies to dissect the physiological responses of osteoblast-like osteosarcoma cells (ROS 17/2.8) to 1,25(OH)2D3 and related metabolites. We conclude the following: 1) the structural requirements for activation of genomic vs. nongenomic pathways by seco-steroid are distinct and likely to involve separate receptors; 2) activation of rapid nongenomic pathways is independent of the long-term regulation of target genes; and 3) 1,25(OH)2D3 and 24,25(OH)2D3 interact at the level of the plasma membrane to regulate Ca+2 permeability. Present studies are aimed toward the understanding of the role of both genomic and nongenomic pathways in osteoblast physiology.
Khoury
R S
RS
Department of Basic Sciences, University of Texas-Houston, Health Science Center 77030, USA.
Weber
J
J
Farach-Carson
M C
MC
D002117:Calcitriol / Q000494:pharmacology / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D016678:Genome; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives / Q000502:physiology*
D014807:Vitamin D; D002117:Calcitriol; D002118:Calcium