A Twist to Bone Development

Abstract

The Runx2 transcription factor controls bone development during early mammalian embryogenesis. However, a delay between Runx2 expression and osteoblast differentiation has suggested that this key transcription factor is held in check by another regulatory protein. Bialek et al. have identified two transcription factors of the Twist family, Twist-1 and -2, that inhibit osteoblast differentiation by blocking Runx2 function, which indicates that initiation of skeletogenesis occurs when an inhibition is relieved. Mouse osteoblasts were found to express Twist proteins before they expressed Runx2. After a decrease in Twist expression, expression of Runx2 gene targets commenced. Premature osteoblast differentiation was observed in mice heterozygous for Twist-1. Runx2 expression was not affected in the heterozygous embryos nor in an osteosarcoma cell line overexpressing Twist proteins. Expression of Twist proteins also decreased Runx2 activity in a transactivation-reporter gene assay. Purified recombinant Twist and Runx proteins interacted directly in vitro, and the authors further mapped the sites of interaction in both proteins. The study also points to premature activation of Runx2 as the molecular defect in Saethre-Chotzen syndrome, a skeletal disorder caused by a haplo-insufficiency in the TWIST locus. P. Bialek, B. Kern, X. Yang, M. Schrock, D. Sosic, N. Hong, H. Wu, K. Yu, D. M. Ornitz, E. N. Olson, M. J. Justice, G. Karsenty, A Twist code determines the onset of osteoblast differentiation. Dev. Cell 6 , 423-435 (2004). [Online Journal]