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/jci200419657
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发表时间：
2004-08-01
影响因子：
15.9
通讯作者：
Yoneda, T
中科院分区：
文献类型：
--
作者：
Ikeda, F;Nishimura, R;Yoneda, T
核因子-kappaB受体激活剂配体(RANKL)在破骨细胞形成和骨吸收中起重要作用。尽管遗传学和生化研究表明RANKL通过激活核因子-kappaB受体激活物及其相关信号分子来调节破骨细胞分化，但RANKL调控破骨细胞分化的分子机制尚未完全确立。我们利用在破骨细胞系中特异表达显性-阴性c-jun的转基因小鼠，研究了由RANKL激活的转录因子c-jun在破骨细胞形成中的作用。我们发现，由于破骨细胞生成受损，转基因小鼠表现出严重的骨化病。阻断c-jun信号也可明显抑制可溶性RANKL诱导的体外破骨细胞分化。过表达活化T细胞核因子1(NFAT1)(NFATc2/NFATp)或NFAT2(NFATc1/NFATc)可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)的多核破骨细胞样细胞。过表达NFAT1还显著反式激活了TRAP基因启动子。NFAT的这些破骨活性被显性负性c-jun的过度表达所取消。重要的是，在转基因小鼠的脾细胞中，NFAT1过表达或可溶性RANKL处理导致的破骨细胞分化和NFAT2表达的诱导显著减少。综上所述，这些结果表明c-jun信号与NFAT协同作用对RANKL调控的破骨细胞分化至关重要。
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.