Kabsun Kim^*, Seoung-Hoon Lee^*, Jung Ha Kim, Yongwon Choi, and Nacksung Kim

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.

^*K.K. and S.-H.L. contributed equally to this work. 

Abstract

NFATc1 has been characterized as a master regulator of nuclear factor κB ligand-induced osteoclast differentiation. Herein, we demonstrate a novel role for NFATc1 as a positive regulator of nuclear factor κB ligand-mediated osteoclast fusion as well as other fusion-inducing factors such as TNF-α. 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 Vo 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.