Sun, 27 Jul 2008 08:18:49 BST CiteULike: heliopais's runx2 http://www.citeulike.org/user/heliopais/tag/runx2 CiteULike.org en-gb Copyright © 2004-2008 citeulike.org http://www.citeulike.org/user/heliopais/article/2718410 <i>Developmental Cell, Vol. 6, No. 3. (March 2004), pp. 423-435.</i><br /><br />Runx2 is necessary and sufficient for osteoblast differentiation, yet its expression precedes the appearance of osteoblasts by 4 days. Here we show that Twist proteins transiently inhibit Runx2 function during skeletogenesis. Twist-1 and -2 are expressed in Runx2-expressing cells throughout the skeleton early during development, and osteoblast-specific gene expression occurs only after their expression decreases. Double heterozygotes for Twist-1 and Runx2 deletion have none of the skull abnormalities observed in Runx2+/- mice, a Twist-2 null background rescues the clavicle phenotype of Runx2+/- mice, and Twist-1 or -2 deficiency leads to premature osteoblast differentiation. Furthermore, Twist-1 overexpression inhibits osteoblast differentiation without affecting Runx2 expression. Twist proteins' antiosteogenic function is mediated by a novel domain, the Twist box, which interacts with the Runx2 DNA binding domain to inhibit its function. In vivo mutagenesis confirms the antiosteogenic function of the Twist box. Thus, relief of inhibition by Twist proteins is a mandatory event precluding osteoblast differentiation. A Twist Code Determines the Onset of Osteoblast Differentiation Peter Bialek Britt Kern Xiangli Yang Marijke Schrock Drazen Sosic Nancy Hong Hua Wu Kai Yu David Ornitz Eric Olson Monica Justice Gerard Karsenty doi:10.1016/S1534-5807(04)00058-9 Developmental Cell, Vol. 6, No. 3. (March 2004), pp. 423-435. 2008-04-25T13:17:16-00:00 2004 Developmental Cell 6 3 423 435 runx2 http://www.citeulike.org/user/heliopais/article/2429851 <i>Medical Hypotheses, Vol. 68, No. 1. (2007), pp. 169-175.</i><br /><br />Summary During the last 10 years, we have witnessed major progress in skeleton biology. Runx2 is an accepted transcription factor essential for osteoblast development from mesenchymal stem cells and maturation into osteocytes and organize crucial events during bone formation. Alternations in Runx2 expression levels are associated with skeletal diseases. In vitro and in vivo studies have reported that multiple integrated complex path ways (such as Wnt/LRP5/[beta]-catenin, BMP/Smads, 1, 25-(OH)2-vitaminD3/VDR/VDRE pathway, etc.) and several regulatory proteins (such as Msx2, Dlx5, Twists, etc.) play critical roles in modulating Runx2 gene expression, activity, and the subsequent bone formation. These findings provide novel insights through controlling osteoblast differentiation to treat osteoporosis or other bone diseases with altered bone mass by stimulating Runx2 expression. Further studies have shown that expression of RUNX2 is initiated from two promoters, the distal P1 promoter and the proximal P2 promoter. The alternative use of promoters gives rise to the genesis of two major protein isoforms with distinct amino termini, named as Runx2-TypeI and Runx2-TypeII. Here, we also review a complex spatio-temporal pattern of two major isoforms expressions and their possible function differences in skeleton development. Advances in Runx2 regulation and its isoforms Ya-Lin Li Zhou-Sheng Xiao doi:10.1016/j.mehy.2006.06.006 Medical Hypotheses, Vol. 68, No. 1. (2007), pp. 169-175. 2008-02-26T14:32:00-00:00 2007 Medical Hypotheses 68 1 169 175 review runx2