NFATc1 induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP) |
| |
Authors: | Kim Kabsun Lee Seoung-Hoon Ha Kim Jung Choi Yongwon Kim Nacksung |
| |
Institution: | National Research Laboratory for Regulation of Bone Metabolism and Disease, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Korea. |
| |
Abstract: | NFATc1 has been characterized as a master regulator of nuclear factor kappaB ligand-induced osteoclast differentiation. Herein, we demonstrate a novel role for NFATc1 as a positive regulator of nuclear factor kappaB ligand-mediated osteoclast fusion as well as other fusion-inducing factors such as TNF-alpha. 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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|