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Molecular and Cellular Biology, April 2006, p. 2955-2964, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.2955-2964.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

CCN1/Cyr61 Is Regulated by the Canonical Wnt Signal and Plays an Important Role in Wnt3A-Induced Osteoblast Differentiation of Mesenchymal Stem Cells

Department of Clinical Hematology, Third Military Medical University, Chongqing 400038, People's Republic of China,¹ Molecular Oncology Laboratory, Department of Surgery, University of Chicago Medical Center, Chicago, Illinois 60637,² Chongqing University of Medical Sciences, Chongqing 400016, People's Republic of China,³ Department of Surgery, St. Paul's Hospital, College of Medicine, Catholic University of Korea, Seoul, South Korea,⁴ Functional Genomics Facilities, University of Chicago, Chicago, Illinois 60637,⁵ Department of Pathology, University of Chicago Hospitals, Chicago, Illinois 60637⁶

Received 16 September 2005/ Returned for modification 28 October 2005/ Accepted 21 January 2006

Marrow mesenchymal stem cells are pluripotent progenitors that can differentiate into bone, cartilage, muscle, and fat cells. Wnt signaling has been implicated in regulating osteogenic differentiation of mesenchymal stem cells. Here, we analyzed the gene expression profile of mesenchymal stem cells that were stimulated with Wnt3A. Among the 220 genes whose expression was significantly changed by 2.5-fold, we found that three members of the CCN family, CCN1/Cyr61, CCN2/connective tissue growth factor (CTGF), and CCN5/WISP2, were among the most significantly up-regulated genes. We further investigated the role of CCN1/Cyr61 in Wnt3A-regulated osteogenic differentiation. We confirmed that CCN1/Cyr61 was up-regulated at the early stage of Wnt3A stimulation. Chromatin immunoprecipitation analysis indicates that CCN1/Cyr61 is a direct target of canonical Wnt/ß-catenin signaling. RNA interference-mediated knockdown of CCN1/Cyr61 expression diminished Wnt3A-induced osteogenic differentiation. Furthermore, exogenously expressed CCN1/Cyr61 was shown to effectively promote mesenchymal stem cell migration. These findings suggest that tightly regulated CCN1/Cyr61 expression may play an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells.

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