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Originally published In Press as doi:10.1074/jbc.M407810200 on October 20, 2004

J. Biol. Chem., Vol. 279, Issue 53, 55958-55968, December 31, 2004
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Connective Tissue Growth Factor (CTGF) Is Regulated by Wnt and Bone Morphogenetic Proteins Signaling in Osteoblast Differentiation of Mesenchymal Stem Cells*

Qing Luo,abc Quan Kang,abcd Weike Si,ae Wei Jiang,a Jong Kyung Park,af Ying Peng,ag Xinmin Li,h Hue H. Luu,a Jeffrey Luo,a Anthony G. Montag,ai Rex C. Haydon,aj and Tong-Chuan Heak

From the aMolecular Oncology Laboratory, Department of Surgery, the University of Chicago Medical Center, Chicago, Illinoid 60637, bthe Children's Hospital of Chongqing University of Medical Sciences, Chongqing 400016, the eDepartment of Clinical Biochemistry, the Third Military Medical University, Chongqing 400038, China, the fDepartment of Surgery, St. Paul's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea, gCommittee on Genetics, hFunctional Genomics Facilities, The University of Chicago, and the iDepartment of Pathology, the University of Chicago Hospitals, Chicago, Illinois 60637

Osteoblast lineage-specific differentiation of mesenchymal stem cells is a well regulated but poorly understood process. Both bone morphogenetic proteins (BMPs) and Wnt signaling are implicated in regulating osteoblast differentiation and bone formation. Here we analyzed the expression profiles of mesenchymal stem cells stimulated with Wnt3A and osteogenic BMPs, and we identified connective tissue growth factor (CTGF) as a potential target of Wnt and BMP signaling. We confirmed the microarray results, and we demonstrated that CTGF was up-regulated at the early stage of BMP-9 and Wnt3A stimulations and that Wnt3A-regulated CTGF expression was {beta}-catenin-dependent. RNA interference-mediated knockdown of CTGF expression significantly diminished BMP-9-induced, but not Wnt3A-induced, osteogenic differentiation, suggesting that Wnt3A may also regulate osteoblast differentiation in a CTGF-independent fashion. However, constitutive expression of CTGF was shown to inhibit both BMP-9- and Wnt3A-induced osteogenic differentiation. Exogenous expression of CTGF was shown to promote cell migration and recruitment of mesenchymal stem cells. Our findings demonstrate that CTGF is up-regulated by Wnt3A and BMP-9 at the early stage of osteogenic differentiation, which may regulate the proliferation and recruitment of osteoprogenitor cells; however, CTGF is down-regulated as the differentiation potential of committed pre-osteoblasts increases, strongly suggesting that tight regulation of CTGF expression may be essential for normal osteoblast differentiation of mesenchymal stem cells.

Received for publication, July 12, 2004 , and in revised form, September 27, 2004.

* The work was supported in part by research grants from the Aircast Foundation, the Brinson Foundation, and the Orthopaedic Research and Education Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

c Both authors contributed equally to this work.

d Recipient of an International Postdoctoral Fellowship F05 AT002014-01 from the National Institutes of Health.

j Recipient of Career Development Grant 1 K08 AR50142-01 from the National Institutes of Health.

k To whom correspondence should be addressed: Molecular Oncology Laboratory, Dept. of Surgery, the University of Chicago Medical Center, 5841 South Maryland Ave., MC3079, Chicago, IL 60637. Tel.: 773-702-7169; Fax: 773-834-4598; E-mail: tche{at}surgery.bsd.uchicago.edu.


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