The architectural organization of the genome and regulatory proteins within the nucleus supports gene expression in a physiologically regulated manner. In osteoblastic cells ligand activation induces a nuclear punctate distribution of the 1 alpha,25-dihydroxy vitamin D3 (1 alpha,25(OH)(2)D-3) receptor (VDR) and promotes its interaction with transcriptional coactivators such as SRC-1, NCoA-62/Skip, and DRIP205. Here, we discuss evidence demonstrating that in osteoblastic cells VDR binds to the nuclear matrix fraction in a 1 alpha,25(OH)(2)D-3-dependent manner. This interaction occurs rapidly after exposure to 1 alpha,25(OH)(2)D-3 and does not require a functional VDR DNA binding domain. The nuclear matrix-bound VDR molecules colocalize with the also nuclear matrix-associated coactivator DRIP205. We propose a model where the rapid association of VDR with the nuclear matrix fraction represents an event that follows 1 alpha,25(OH)(2)D-3-dependent nuclear localization of VDR, but that precedes 1 alpha,25(OH)(2)D-3-dependent transcriptional upregulation at target genes. (C) 2010 Elsevier Ltd. All rights reserved.