Functional cooperativity between osteoblast transcription factors: evidence for the importance of subnuclear...

The accompanying article by Drs. Lian and Stein describes current thinking on how genes are organized in the nucleus and suggests that subnuclear localization is critical for the control of gene expression in bone. In particular, it is proposed that a major function of the osteoblast transcription factor, Runx2, is to tether genes that are active in osteoblasts to the nuclear matrix and serve as an organizing center for other nuclear factors which together form osteoblast-specific transcriptional units. Although it is still not established that the nuclear matrix localization function of Runx2 is essential for all its biological activities, there is no question that this factor plays a central role in mediating the response of osteoblasts to a variety of signals, as would be expected if Runx2 were involved in organizing the transcriptional apparatus. As will be discussed, Runx2 is required for the response of osteoblasts to other lineage-specific transcription factors and signals initiated by extracellular matrix-integrin binding, growth factors, hormones, and morphogens. We hypothesize that Runx2 transduces this wide range of responses by cycling between active, phosphorylated and a less active, dephosphorylated states which can selectively interact with other nuclear factors to form macromolecular complexes active in transcription. The possible relationship between these complexes and the subnuclear localization of the osteoblast transcriptional apparatus will also be discussed.