Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation
Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation
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DOI：
10.1172/jci19657
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发表时间：
2004-08
影响因子：
15.9
通讯作者：
Fumiyo Ikeda;R. Nishimura;T. Matsubara;Sakae Tanaka;J. Inoue;S. Reddy;K. Hata;Kenji Yamashita
中科院分区：
文献类型：
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作者：
Fumiyo Ikeda;R. Nishimura;T. Matsubara;Sakae Tanaka;J. Inoue;S. Reddy;K. Hata;Kenji Yamashita
NF-κ B受体活化因子配体（RANKL）在破骨细胞形成和骨吸收中起重要作用。尽管遗传和生物化学研究表明RANKL通过激活NF-κ B受体激活剂和相关信号分子调节破骨细胞分化，但RANKL调节破骨细胞分化的分子机制尚未完全确立。我们使用在破骨细胞谱系中特异性表达显性阴性c-Jun的转基因小鼠，研究了转录因子c-Jun（由RANKL激活）在破骨细胞生成中的作用。我们发现，转基因小鼠表现出严重的骨硬化症，由于破骨细胞生成受损。阻断c-Jun信号传导也显著抑制可溶性RANKL诱导的体外破骨细胞分化。活化T细胞核因子1（NFAT 1）（NFATc 2/NFATp）或NFAT 2（NFATc 1/NFATc）的过表达促进破骨细胞前体细胞分化为抗酒石酸酸性磷酸酶阳性（TRAP阳性）多核破骨细胞样细胞，即使在RANKL不存在的情况下。过表达NFAT 1也显著地反式激活TRAP基因启动子。NFAT的这些破骨细胞生成活性被显性阴性c-Jun的过表达所废除。重要的是，在转基因小鼠的脾细胞中，破骨细胞分化和NFAT 1过表达或可溶性RANKL处理诱导的NFAT 2表达显著减少。总的来说，这些结果表明，c-Jun信号与NFAT的合作是至关重要的RANKL调节破骨细胞分化。
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.