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J. Biol. Chem., Vol. 278, Issue 49, 48745-48753, December 5, 2003

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RANKL and Vascular Endothelial Growth Factor (VEGF) Induce Osteoclast Chemotaxis through an ERK1/2-dependent Mechanism^*

Kim Henriksen, Morten Karsdal, Jean-Marie Delaissé, and Michael T. Engsig

From the Nordic Bioscience, Herlev DK-2730, Denmark

Development of bone depends on a continuous supply of bone-degrading osteoclasts. Although several factors such as the matrix metalloproteinases and the integrins have been shown to be important for osteoclast recruitment, the mechanism of action remains poorly understood. In this study we investigated the molecular mechanisms homing osteoclasts to their future site of resorption during bone development. We show that RANKL and VEGF, two cytokines known to be present in bone, possess chemotactic properties toward osteoclasts cultured in modified Boyden chambers. Furthermore, in ex vivo cultures of embryonic murine metatarsals, a well established model of osteoclast recruitment, antagonists of RANKL and VEGF reduced calcium release, showing that both cytokines play roles during bone development. In cultures of purified osteoclasts both RANKL and VEGF induced phosphorylation of ERK1/2 MAP kinase. M-CSF, a well-known chemoattractant of osteoclast, also induced activation of ERK1/2, although this activation followed a kinetic pattern differing from that of RANKL and VEGF. RANKL and VEGF-induced, but not M-CSF-induced, osteoclast invasion was completely blocked by the specific inhibitor of ERK1/2 phosphorylation, PD98059. In addition, PD98059 was able to inhibit calcium release in cultures of embryonic metatarsals. In contrast, PD98059 was unable to abrogate the RANKL-induced calcium release in the tibia model, demonstrating that only some of the RANKL functions on osteoclast physiology are regulated through the ERK1/2 pathway. Taken together, these results show that RANKL and VEGF, in addition to their role in osteoclast differentiation and activation of resorption, are important components of the processes regulating osteoclast chemotaxis.

Received for publication, August 19, 2003 , and in revised form, September 9, 2003.

^* 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.

To whom correspondence should be addressed: Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730 Herlev, Denmark. Tel.: 45-30-29-42-42; Fax: 45-44-52-52-51; E-mail: kim_henriksen2{at}yahoo.dk.

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