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J. Biol. Chem., Vol. 282, Issue 37, 26656-26664, September 14, 2007

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IMPLICATIONS FOR OSTEOLYTIC BONE METASTASES^*

Ji Zhu, Xun Jia, Guozhi Xiao, Yibin Kang^¶, Nicola C. Partridge, and Ling Qin¹

From the Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, the Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15240, and the ^¶Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544

Epidermal growth factor (EGF)-like ligands and their receptors constitute one of the most important signaling networks functioning in normal tissue development and cancer biology. Recent in vivo mouse models suggest this signaling network plays an essential role in bone metabolism. Using a coculture system containing bone marrow macrophage and osteoblastic cells, here we report that EGF-like ligands stimulate osteoclastogenesis by acting on osteoblastic cells. This stimulation is not a direct effect because osteoclasts do not express functional EGF receptors (EGFRs). Further studies reveal that EGF-like ligands strongly regulate the expression of two secreted osteoclast regulatory factors in osteoblasts by decreasing osteoprotegerin (OPG) expression and increasing monocyte chemoattractant protein 1 (MCP1) expression in an EGFR-dependent manner and consequently stimulate TRAP-positive osteoclast formation. Addition of exogenous OPG completely inhibited osteoclast formation stimulated by EGF-like ligands, while addition of a neutralizing antibody against MCP-1 exhibited partial inhibition. Coculture with bone metastatic breast cancer MDA-MB-231 cells had similar effects on the expression of OPG and MCP1 in the osteoblastic cells, and those effects could be partially abolished by the EGFR inhibitor PD153035. Because a high percentage of human carcinomas express EGF-like ligands, our findings suggest a novel mechanism for osteolytic lesions caused by cancer cells metastasizing to bone.

Received for publication, June 20, 2007 , and in revised form, July 17, 2007.

^* This work was supported in part by National Institutes of Health Grant K01DK071988 (to L. Q.), the National Osteoporosis Foundation (to L. Q.), and a New Jersey Stem Cell Research grant (to L. Q.). 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 Figs. S1 and S2.

¹ To whom correspondence should be addressed: Dept. of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854. Tel.: 732-235-2821; Fax: 732-235-5038; E-mail: qinl1{at}umdnj.edu.

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