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¹ Department of Biological Sciences and Biotechnology, State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, China
² Northwest Agriculture and Forestry University, Shaanxi, Yangling 712100, China
³ Beijing Key Laboratory, College of Life Sciences, Beijing Normal University, Beijing 100875, China
⁴ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto M5G 1L5, Canada
⁵ Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033
⁶ Department of Orthopaedics, University of Rochester, Rochester, NY 14642

Correspondence to Zhijie Chang: zhijiec{at}tsinghua.edu.cn

Runx2, an essential transactivator for osteoblast differentiation, is tightly regulated at both the transcriptional and posttranslational levels. In this paper, we report that CHIP (C terminus of Hsc70-interacting protein)/STUB1 regulates Runx2 protein stability via a ubiquitination-degradation mechanism. CHIP interacts with Runx2 in vitro and in vivo. In the presence of increased Runx2 protein levels, CHIP expression decreases, whereas the expression of other E3 ligases involved in Runx2 degradation, such as Smurf1 or WWP1, remains constant or increases during osteoblast differentiation. Depletion of CHIP results in the stabilization of Runx2, enhances Runx2-mediated transcriptional activation, and promotes osteoblast differentiation in primary calvarial cells. In contrast, CHIP overexpression in preosteoblasts causes Runx2 degradation, inhibits osteoblast differentiation, and instead enhances adipogenesis. Our data suggest that negative regulation of the Runx2 protein by CHIP is critical in the commitment of precursor cells to differentiate into the osteoblast lineage.

X. Li, M. Huang, and H. Zheng contributed equally to this paper.

Abbreviations used in this paper: AA, ascorbic acid; β-GP, β-glycerophosphate; BMP, bone morphogenetic protein; BSP, bone sialoprotein; OCN, osteocalcin; TPR, tetratricopeptide repeat.

© 2008 Li et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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