TISSUE-SPECIFIC AND VITAMIN-D RESPONSIVE GENE-EXPRESSION IN BONE

Studies of gene expression in bone have adopted a number of molecular approaches that seek to determine those cis and trans-acting factors r esponsible for the development and physiological regulation of this un ique tissue. The majority of studies have been performed in vitro, foc ussing on the expression of genes such as osteocalcin, bone sialoprote in and type I collagen which demonstrate restricted or altered express ion patterns in osteoblasts. These studies have demonstrated a large n umber of cis and traits acting factors that modulate the tissue specif ic and vitamin D responsive expression of these genes. These include t he response elements and regions mediating basal and vitamin D depende nt transcription of these genes as well as some of the transcription f actors that bind to these regions and the nucleosomal organisation of these genes within a nuclear framework. In vivo studies, including the introduction of transgenes into transgenic mice, extend these in vitr o observations within a physiological context. However, in part due to limitations in each approach, these in vitro and in vivo studies are yet to accurately define all the necessary cis and trans-acting factor s required for tissue specific and vitamin D responsive gene expressio n. Advances have been made in identifying many cis-acting regions with in the flanking regions of these genes that are responsible for their restricted expression patterns, but a vector incorporating all the nec essary cis-acting regions capable of directing gene expression indepen dent of integration site has not yet been described. Similarly, trans- acting factors that determine the developmental destiny of osteoblast progenitors and the restricted expression of these genes remain elusiv e and, despite advances in the understanding of protein-DNA interactio ns at vitamin D response elements contained within these genes, furthe r intermediary factors that interact with the transcriptional machiner y to modulate vitamin D responsiveness need to be identified.