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タイトル: Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-requlated osteoclast differentiation
著者: Ikeda, Fumiyo
Nishimura, Riko
Matsubara, Takuma
Tanaka, Sakae
Inoue, Jun-ichiro
Reddy, Sakamuri V.
Hata, Kenji
Yamashita, Kenji
Hiraga, Toru
Watanabe, Toshiyuki
Kukita, Toshio
Yoshioka, Katsuji link image link image
Rao, Anjana
Yoneda, Toshiyuki
善岡, 克次
発行日: 2004年 8月
出版社(者): American Society for Clinical Investigation
雑誌名: Journal of Clinical Investigation
ISSN: 0021-9738
巻: 114
号: 4
開始ページ: 475
終了ページ: 484
抄録: Receptor activator of NF-κB ligand (RANKL) plays an essential role in osteoclast formation and bone resorption. Although genetic and biochemical studies indicate that RANKL regulates osteoclast differentiation by activating receptor activator of NF-κB and associated signaling molecules, the molecular mechanisms of RANKL-regulated osteoclast differentiation have not yet been fully established. We investigated the role of the transcription factor c-Jun, which is activated by RANKL, in osteoclastogenesis using transgenic mice expressing dominant-negative c-Jun specifically in the osteoclast lineage. We found that the transgenic mice manifested severe osteopetrosis due to impaired osteoclastogenesis. Blockade of c-Jun signaling also markedly inhibited soluble RANKL-induced osteoclast differentiation in vitro. Overexpression of nuclear factor of activated T cells 1 (NFAT1) (NFATc2/ NFATp) or NFAT2 (NFATc1/NFATc) promoted differentiation of osteoclast precursor cells into tartrate-resistant acid phosphatase-positive (TRAP-positive) multinucleated osteoclast-like cells even in the absence of RANKL. Overexpression of NFAT1 also markedly transactivated the TRAP gene promoter. These osteoclastogenic activities of NFAT were abrogated by overexpression of dominant-negative c-Jun. Importantly, osteoclast differentiation and induction of NFAT2 expression by NFAT1 overexpression or soluble RANKL treatment were profoundly diminished in spleen cells of the transgenic mice. Collectively, these results indicate that c-Jun signaling in cooperation with NFAT is crucial for RANKL-regulated osteoclast differentiation.
DOI: 10.1172/JCI200419657
URI: http://hdl.handle.net/2297/16791
関連URI: http://dx.doi.org/10.1172/JCI200419657
http://www.jci.org/articles/view/19657
資料種別: Journal Article
権利関係: Copyright © 2004, The American Society for Clinical Investigation
版表示: publisher
出現コレクション:1. 査読済論文

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