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NFATc1 Induces Osteoclast Fusion Via Up-Regulation of Atp6v0d2 and the Dendritic Cell-Specific Transmembrane Protein (DC-STAMP)

National Research Laboratory for Regulation of Bone Metabolism and Disease (K.K., J.H.K., N.K.), Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Korea; and Department of Pathology and Laboratory Medicine (S.-H.L., Y.C.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19014

Address all correspondence and requests for reprints to: Nacksung Kim, National Research Laboratory for Regulation of Bone Metabolism and Disease, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Hak-Dong 5, Dong-Ku, Gwangju 501-746, Korea. E-mail: nacksung{at}jnu.ac.kr.

NFATc1 has been characterized as a master regulator of nuclear factor B ligand-induced osteoclast differentiation. Herein, we demonstrate a novel role for NFATc1 as a positive regulator of nuclear factor B ligand-mediated osteoclast fusion as well as other fusion-inducing factors such as TNF-. Exogenous overexpression of a constitutively active form of NFATc1 in bone marrow-derived monocyte/macrophage cells (BMMs) induces formation of multinucleated osteoclasts as well as the expression of fusion-mediating molecules such as the d2 isoform of vacuolar ATPase V_o domain (Atp6v0d2) and the dendritic cell-specific transmembrane protein (DC-STAMP). Moreover, inactivation of NFATc1 by cyclosporin A treatment attenuates expression of Atp6v0d2 and DC-STAMP and subsequent fusion process of osteoclasts. We show that NFATc1 binds to the promoter regions of Atp6v0d2 and DC-STAMP in osteoclasts and directly induces their expression. Furthermore, overexpression of Atp6v0d2 and DC-STAMP rescues cell-cell fusion of preosteoclasts despite reduced NFATc1 activity. Our data indicate for the first time that the NFATc1/Atp6v0d2 and DC-STAMP signaling axis plays a key role in the osteoclast multinucleation process, which is essential for efficient bone resorption.

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