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J. Biol. Chem., Vol. 279, Issue 14, 13984-13992, April 2, 2004

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The Calcineurin/Nuclear Factor of Activated T Cells Signaling Pathway Regulates Osteoclastogenesis in RAW264.7 Cells^*

Hiroaki Hirotani, Nathaniel A. Tuohy, Je-Tae Woo, Paula H. Stern¶, and Neil A. Clipstone||**

From the Departments of Molecular Pharmacology and Biological Chemistry, and ^||Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Although best known for its role in T lymphocyte activation, the calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway is also known to be involved in a wide range of other biological responses in a variety of different cell types. Here we have investigated the role of the calcineurin/NFAT signaling pathway in the regulation of osteoclast differentiation. Osteoclasts are bone-resorbing multinucleated cells that are derived from the monocyte/macrophage cell lineage after stimulation with a member of the tumor necrosis factor family of ligands known as receptor activator of nuclear factor-B ligand (RANKL). We now report that inhibition of calcineurin with either the immunosuppressant drugs cyclosporin A and FK506, or the retrovirally mediated ectopic expression of a specific calcineurin inhibitory peptide, all potently inhibit the RANKL-induced differentiation of the RAW264.7 monocyte/macrophage cell line into mature multinucleated osteoclasts. In addition, we find that NFAT family members are expressed in RAW264.7 cells and that their expression is up-regulated in response to RANKL stimulation. Most importantly, we find that ectopic expression of a constitutively active, calcineurin-independent NFATc1 mutant in RAW264.7 cells is sufficient to induce these cells to express an osteoclast-specific pattern of gene expression and differentiate into morphologically distinct, multinucleated osteoclasts capable of inducing the resorption of a physiological mineralized matrix substrate. Taken together, these data define calcineurin as an essential downstream effector of the RANKL-induced signal transduction pathway leading toward the induction of osteoclast differentiation and furthermore, indicate that the activation of the NFATc1 transcription factor is sufficient to initiate a genetic program that results in the specification of the mature functional osteoclast cell phenotype.

Received for publication, December 20, 2002 , and in revised form, December 8, 2003.

^* This work was supported by National Institutes of Health Grant R29 GM55292 (to N. A. C.) and a grant from the Chicago chapter of the National Arthritis Foundation and Pilot Project P60 AR30692 (to P. H. S). 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.

Present address: Dept. of Oral and Maxillofacial Surgical Science, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.

¶ To whom correspondence may be addressed: Dept. of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Chicago, IL 60611. Tel.: 312-503-8290; Fax: 312-503-5349; E-mail: p-stern{at}northwestern.edu. ^** To whom correspondence may be addressed: Dept. of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Chicago, IL 60611. Tel.: 312-503-8233; Fax: 312-503-1339; E-mail: n-clipstone{at}northwestern.edu.

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