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J. Biol. Chem., Vol. 281, Issue 26, 17961-17967, June 30, 2006

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Vascular Endothelial Growth Factor-D Activates VEGFR-3 Expressed in Osteoblasts Inducing Their Differentiation^*

Maurizio Orlandini, Adriano Spreafico, Monia Bardelli, Marina Rocchigiani, Ahmad Salameh, Sara Nucciotti, Caterina Capperucci, Bruno Frediani, and Salvatore Oliviero¹

From the Dipartimento di Biologia Molecolare and the Dipartimento di Medicina Clinica e Scienze Immunologiche, Sez. Reumatologia, Universita' degli Studi di Siena, 53100 Siena, Italy

Vascular endothelial growth factor (VEGF)-D is a member of the VEGF family of angiogenic growth factors that recognizes and activates the vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3 on blood and/or lymphatic vessels. We show that in the long bones of newborn mice, VEGF-D and VEGFR-3 are expressed in the osteoblasts of the growing plate. The treatment of primary human osteoblasts with recombinant VEGF-D induces the expression of osteocalcin and the formation of mineralized nodules in a dose-dependent manner. A monoclonal neutralizing antibody, anti-VEGF-D, or silencing of VEGFR-3 by lentiviral-mediated expression of VEGFR-3 small hairpin RNA affects VEGF-D-dependent osteocalcin expression and nodule formation. Moreover, in primary human osteoblasts, VEGF-D expression is under the control of VEGF, and inhibition of VEGF-D/VEGFR-3 signaling, by monoclonal antibodies or VEGFR-3 silencing, affects VEGF-dependent osteoblast differentiation. These experiments establish that VEGF-D/VEGFR-3 signaling plays a critical role in osteoblast maturation and suggest that VEGF-D is a downstream effector of VEGF in osteogenesis.

Received for publication, January 17, 2006 , and in revised form, March 22, 2006.

^* This study was supported by grants from Associazione Italiana Ricerca sul Cancro, Ministero Italiano dell'Istruzione, dell'Università e della Ricerca, and Fondazione Monte dei Paschi di Siena. 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 To whom correspondence should be addressed: Dipartimento di Biologia Molecolare, Universita' di Siena, Via Fiorentina 1, 53100 Siena, Italy. Tel.: 39-0577-234931; Fax: 39-0577-234903; E-mail: oliviero{at}unisi.it.

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