Transcriptional activation through the vitamin D receptor in osteoblasts.

Abstract

Osteoblasts are bone-forming cells that play an essential role in the development and maintenance of a mineralized bone extracellular matrix and they are target cells for vitamin D. Osteoblasts express vitamin D receptors (VDR) and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] regulates the expression of osteoblastic-specific genes such as osteocalcin and osteopontin. VDR is a ligand-inducible transcription factor which heterodimerizes with retinoid X receptor (RXR) and binds as a heterodimer to vitamin D-responsive elements (VDREs) in the promoter region of vitamin-D responsive genes, ultimately leading to their increased transcription. Important structural aspects of the VDR and the role that each functional domain plays in mediating VDR action in the context of the osteoblast are discussed. A summary of the potential molecular mechanisms involved in VDR-activated transcription highlighting the importance of interactions between the VDR and general transcription factors (GTFs), TBP-associated factors (TAFIIs), and nuclear receptor coactivator and corepressor proteins are reviewed. These interactions have a role in linking the VDR-RXR heterodimer to the transcriptional pre-initiation complex (PIC) and in regulating the transcription of vitamin D-dependent genes. In addition, recent findings suggest that these interactions are important for regulating the accessibility to promoters by modifying the acetylation state of histones. The complex interplay that occurs between VDR and these various factors to determine the overall transcriptional activity of vitamin D-responsive genes will be summarized.