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Abstract
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/β-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.
Supplemental material for this article may be found at http://mcb.asm.org/.
We thank Xi He of Harvard Medical School for providing the Dkk1 construct. We also thank Lester F. Lau of the University of Illinois at Chicago for helpful discussion.
The work was supported in part by research grants from the Brinson Foundation, the Orthopaedic Research and Education Foundation, the American Cancer Society, and the National Institutes of Health. T.-C.H. was a recipient of the Overseas Young Investigator Collaboration Award of the Natural Science Foundation of China (NSFC award no. 30228026) and a recipient of the Bayn Scholar of Chonqing Municipality, China.