Nongenomic Actions of 1,25-Dihydroxyvitamin D3 in Rat Osteosarcoma Cells: Structure-Function Studies Using Ligand Analogs*

Osteoblast-like osteosarcoma cells (ROS 17/2.8) display a rapid transmembrane influx of extracellular calcium after stimulation by 1,25-dihydroxyvitamin D3 [l,25-(OH)2D3] that is mediated largely by the opening of voltage-gated calcium channels. These cells also constitute ely express high numbers (>18,000/cell) of nuclear receptors for this seco-steroid hormone that are involved in the modulation of genomic activity in the osteoblast and in the up-regulation of transcript ion of osteoblast- specific genes such as osteocalcin. The objective of this study was to determine the structural hierarchy of vitamin D3 analogs with regard to their efficacy as molecular transducers of the genomic and nongenomic pathways that are activated upon treatment of osteoblasts with 1,25-(0H)2D3. To test the structural features of the agonist required for initiation of these distinct pathways, a series of ligand analogs and naturally occurring metabolites of 1,25-(OH)2D3 were used that contain Aring, D-ring, and side-chain mo...