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J. Biol. Chem., Vol. 282, Issue 37, 26746-26753, September 14, 2007

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Vascular Endothelial Growth Factor (VEGF)-induced Up-regulation of CCN1 in Osteoblasts Mediates Proangiogenic Activities in Endothelial Cells and Promotes Fracture Healing^*

Athanasios N. Athanasopoulos¹, Darius Schneider¹, Tanja Keiper, Volker Alt, Usha R. Pendurthi^¶, Ute M. Liegibel, Ulrike Sommer, Peter P. Nawroth, Christian Kasperk, and Triantafyllos Chavakis^||2

From the Department of Internal Medicine I, University Heidelberg, D-69120 Heidelberg, the Department of Trauma Surgery, University Hospital Giessen-Marburg, D-35385 Giessen, Germany, the ^¶Biomedical Research Division, The University of Texas Health Center at Tyler, Tyler, Texas, and the ^||Experimental Immunology Branch (EIB), NCI, National Institutes of Health, Bethesda, Maryland 20992

Angiogenesis is indispensable during fracture repair, and vascular endothelial growth factor (VEGF) is critical in this process. CCN1 (CYR61) is an extracellular matrix signaling molecule that has been implicated in neovascularization through its interactions with several endothelial integrin receptors. CCN1 has been shown to be up-regulated during the reparative phase of fracture healing; however, the role of CCN1 therein remains unclear. Here, the regulation of CCN1 expression in osteoblasts and the functional consequences thereof were studied. Stimulation of osteoblasts with VEGF resulted in a dose- and time-dependent up-regulation of CCN1 mRNA and protein. An up-regulation of both cell surface-associated CCN1 as well as extracellular matrix-associated CCN1 in osteoblasts was found. The supernatant of VEGF-prestimulated osteoblasts was chemotactic for endothelial cells, increasing their migration and stimulated capillary-like sprout formation. These effects could be attributed to the presence of CCN1 in the osteoblast supernatant as they were prevented by an antibody against CCN1 or by small interfering RNA-mediated knockdown of osteoblast CCN1. Moreover, the supernatant of VEGF-prestimulated osteoblasts induced angiogenesis in Matrigel plugs in vivo in a CCN1-dependent manner. In addition, blockade of CCN1 prevented bone fracture healing in mice. Taken together, the present work demonstrates a potential paracrine loop consisting of the VEGF-mediated up-regulation of CCN1 in osteoblasts that attracts endothelial cells and promotes angiogenesis. Such a loop could be operative during fracture healing.

Received for publication, June 25, 2007 , and in revised form, July 9, 2007.

^* 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.

¹ Both authors contributed equally to the work.

² To whom correspondence should be addressed: EIB, NCI, National Institutes of Health, 10 Center Dr., Rm. 4B17, Bethesda, MD 20892. Tel.: 301-451-2104; Fax: 301-496-0887; E-mail: chavakist{at}mail.nih.gov.

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