THE 1,25-DIHYDROXYVITAMIN D-3 (VD) ANALOGS MC903, EB1089 AND KH1060 ACTIVATE THE VD RECEPTOR - HOMODIMERS SHOW HIGHER LIGAND SENSITIVITY THAN HETERODIMERS WITH RETINOID X RECEPTORS

The nuclear receptor for 1,25-dihydroxyvitamin D-3 (VD), VDR, belongs to the nuclear receptor superfamily. This ligand-inducible transcripti on factor mediates the genomic VD signalling pathways by binding to sp ecific response elements in the promoter region of VD regulated genes. Two types of natural VD response elements are used as models for the VDR-mediated transcriptional activation: one is bound by VDR-homodimer s and is found in the human osteocalcin gene promoter, and the other i s bound by heterodimers of VDR with retinoid X receptors (RXRs) as in the mouse osteopontin promoter. Here, we demonstrate that the VD analo gues MC903, EB1089 and KH1060, previously shown to be potent regulator s of proliferation and differentiation, are able to act as ligands for VDR and replace VD as a ligand in both nuclear signalling pathways. W e found that they have different potency and sensitivity in their abil ity to stimulate the hormone-dependent promoter element. MC903 and EB1 089 provide about 20% higher induction of gene activity than VD in a g ene reporter system, whereas KH1060 was more sensitive, inducing trans cription at about 100-fold lower doses than VD. Interestingly, VD and its analogues induce VDR homodimer-mediated gene activity at a 3- to 4 -fold lower concentration than that of VDR-RXR heterodimers. This sugg ests that the ligand concentration is an additional regulatory level i n the discrimination between signalling pathways involving homo- and h eterodimeric hormone receptors.