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J. Biol. Chem., Vol. 280, Issue 16, 16163-16169, April 22, 2005

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MCP-1 Is Induced by Receptor Activator of Nuclear Factor-B Ligand, Promotes Human Osteoclast Fusion, and Rescues Granulocyte Macrophage Colony-stimulating Factor Suppression of Osteoclast Formation^*

Michael S. Kim, Christopher J. Day, and Nigel A. Morrison¶

From the School of Medical Science, Griffith University Gold Coast Campus, Queensland 4215, Australia

Human osteoclast formation from monocyte precursors under the action of receptor activator of nuclear factor-B ligand (RANKL) was suppressed by granulocyte macrophage colony-stimulating factor (GM-CSF), with down-regulation of critical osteoclast-related nuclear factors. GM-CSF in the presence of RANKL and macrophage colony-stimulating factor resulted in mononuclear cells that were negative for tartrate-resistant acid phosphatase (TRAP) and negative for bone resorption. CD1a, a dendritic cell marker, was expressed in GM-CSF, RANKL, and macrophage colony-stimulating factor-treated cells and absent in osteoclasts. Microarray showed that the CC chemokine, monocyte chemotactic protein 1 (MCP-1), was profoundly repressed by GM-CSF. Addition of MCP-1 reversed GM-CSF suppression of osteoclast formation, recovering the bone resorption phenotype. MCP-1 and chemokine RANTES (regulated on activation normal T cell expressed and secreted) permitted formation of TRAP-positive multinuclear cells in the absence of RANKL. However, these cells were negative for bone resorption. In the presence of RANKL, MCP-1 significantly increased the number of TRAP-positive multinuclear bone-resorbing osteoclasts (p = 0.008). When RANKL signaling through NFATc1 was blocked with cyclosporin A, both MCP-1 and RANTES expression was down-regulated. Furthermore, addition of MCP-1 and RANTES reversed the effects of cyclosporin A and recovered the TRAP-positive multinuclear cell phenotype. Our model suggests that RANKL-induced chemokines are involved in osteoclast differentiation at the stage of multinucleation of osteoclast precursors and provides a rationale for increased osteoclast activity in inflammatory conditions where chemokines are abundant.

Received for publication, November 10, 2004 , and in revised form, February 14, 2005.

^* 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.

Supported by a postgraduate fellowship from Griffith University.

Supported by a postgraduate fellowship from the Australian Research Council.

^¶ To whom correspondence should be addressed: School of Medical Science, Griffith University, Gold Coast Campus, PMB50 GCMC QLD 9726, Australia. Tel.: 61-7-5552-8330; Fax: 61-7-5552-8908; E-mail: N.Morrison{at}griffith.edu.au.

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