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J. Biol. Chem., Vol. 283, Issue 19, 13491-13499, May 9, 2008

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VEGF-C, a Lymphatic Growth Factor, Is a RANKL Target Gene in Osteoclasts That Enhances Osteoclastic Bone Resorption through an Autocrine Mechanism^*

Qian Zhang¹, Ruolin Guo¹, Yan Lu, Lan Zhao, Quan Zhou, Edward M. Schwarz, Jing Huang, Di Chen, Zheng-Gen Jin^¶, Brendan F. Boyce, and Lianping Xing²

From the Department of Pathology and Laboratory Medicine,Center for Musculoskeletal Research, and ^¶Department of Medicine, University of Rochester Medical Center, Rochester, New York 14642

Osteoclasts are bone-resorbing cells, but they also secrete and respond to cytokines. Here, we test the hypothesis that osteoclasts secrete the lymphatic growth factor, VEGF-C, to increase their resorptive activity. Osteoclasts and osteoclast precursors were generated by culturing splenocytes with macrophage colony-stimulating factor and RANKL from wild-type, NF-Bp50^-/-/p52^-/-, and Src^-/- mice. Expression of VEGFs was measured by real time reverse transcription-PCR, Western blotting, and immunostaining. The effect of VEGF-C signaling on osteoclast function was determined by osteoclastogenesis and pit assays. RANKL increased the expression of VEGF-C but not of other VEGFs in osteoclasts and their precursors. RANKL-induced VEGF-C expression was reduced in NF-Bp50^-/-/p52^-/- precursors or wild-type cells treated with an NF-B inhibitor. VEGF-C directly stimulated RANKL-mediated bone resorption, which was reduced by the VEGF-C-specific receptor blocker, VEGFR3:Fc. Osteoclasts express VEGFR3, and VEGF-C stimulated Src phosphorylation in osteoclasts. VEGF-C-mediated bone resorption was abolished in Src^-/- osteoclasts or cells treated with an Src inhibitor. We conclude that RANKL stimulates osteoclasts and their precursors to release VEGF-C through an NF-B-dependent mechanism, indicating that VEGF-C is a new RANKL target gene in osteoclasts and functions as an autocrine factor regulating osteoclast activity.

Received for publication, September 26, 2007 , and in revised form, March 17, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants PHS AR48697 and AR53586 (to L. X.) and AR43510 (to B. F. B.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Fig. S1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, 601 Elmwood Ave, Box 626, Rochester, NY 14642. Tel.: 585-273-4090; Fax: 585-756-4468; E-mail: Lianping_xing{at}urmc.rochester.edu.

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