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Vitamin D Metabolites Modulate Osteoblast Activity by Ca⁺² Influx-Independent Genomic and Ca⁺² Influx-Dependent Nongenomic Pathways^1,2,

The University of Texas - Houston, Health Science Center, Dental Branch, Department of Basic Sciences, Section of Biochemistry, Houston, TX 77030

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.

KEY WORDS: • osteoblasts • vitamin D metabolites • calcium influx • bone

¹ Presented as part of the symposium "Pleiotropic Actions of Vitamin D" given at the Experimental Biology '94 meeting, Anaheim, CA, on April 26, 1994. This symposium was sponsored by the American Institute of Nutrition. Guest editor for this symposium was Anthony W. Norman, University of California, Riverside, CA.

² Supported by DE-10318.

³ To whom correspondence should be addressed: Department of Basic Sciences, Section of Biochemistry, University of Texas—Houston, Dental Branch, DBB 3.108, 6516 John Freeman Ave., Houston, TX 77030.

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