論文 - 詳細
| RRC ID | 1377 |
|---|---|
| 著者 | Ikeda F, Nishimura R, Matsubara T, Tanaka S, Inoue J, Reddy SV, Hata K, Yamashita K, Hiraga T, Watanabe T, Kukita T, Yoshioka K, Rao A, Yoneda T. |
| タイトル | Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation. |
| ジャーナル | J Clin Invest |
| Abstract |
Receptor activator of NF-kappaB 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-kappaB 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. |
| 巻・号 | 114(4) |
| ページ | 475-84 |
| 公開日 | 2004-8-1 |
| DOI | 10.1172/JCI19657 |
| PMID | 15314684 |
| PMC | PMC503767 |
| MeSH | Adenoviridae / genetics Animals Animals, Newborn Anthracenes / pharmacology Bone Marrow Cells / cytology Bone Marrow Cells / drug effects Bone Marrow Cells / metabolism COS Cells Carrier Proteins / genetics Carrier Proteins / metabolism* Carrier Proteins / pharmacology Cell Differentiation* Cell Line Cell Lineage Chlorocebus aethiops DNA-Binding Proteins / metabolism* Enzyme Activation / drug effects Gene Expression Regulation Genes, Reporter Membrane Glycoproteins / genetics Membrane Glycoproteins / metabolism* Membrane Glycoproteins / pharmacology Mice Mice, Inbred C57BL Mice, Transgenic Monocytes / cytology Monocytes / drug effects Monocytes / metabolism NFATC Transcription Factors Nuclear Proteins* Osteoclasts / drug effects Osteoclasts / metabolism* Osteoclasts / pathology Promoter Regions, Genetic Proto-Oncogene Proteins c-jun / genetics Proto-Oncogene Proteins c-jun / metabolism* RANK Ligand Receptor Activator of Nuclear Factor-kappa B Signal Transduction / drug effects* Transcription Factors / metabolism* Transcriptional Activation |
| IF | 11.864 |
| 引用数 | 344 |
| WOS 分野 | MEDICINE, RESEARCH & EXPERIMENTAL |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 遺伝子材料 | pBS rcjun-1 Rat c-Jun protooncogene (RDB1130) |
| ヒト・動物細胞 | RAW 264(RCB0535) COS-7(RCB0539) |