cIAP1/2 negatively regulate RANKL-induced osteoclastogenesis through the inhibition of NFATc1 expression
cIAP1/2 negatively regulate RANKL-induced osteoclastogenesis through the inhibition of NFATc1 expression
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cIAP1/2 通过抑制 NFATc1 表达负向调节 RANKL 诱导的破骨细胞生成
DOI：
10.1111/gtc.12012
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发表时间：
2012
期刊：
影响因子：
2.1
通讯作者：
Noritaka Yamaguchi
中科院分区：
文献类型：
--
作者：
Yamakoshi;K.;Hara;E.;村田美樹;村田 美樹;Miki Murata;村田 美樹;村田 美樹;村田美樹;Noritaka Yamaguchi
核因子 κB 受体激活剂 (RANK) 是肿瘤坏死因子受体超家族 (TNFRSF) 的成员，通过激活 NF-κB 和 MAPK 途径诱导 NFATc1 的表达，从而触发破骨细胞生成。凋亡蛋白 1 和 2 (cIAP1/2) 的细胞抑制剂是泛素 E3 连接酶，参与 TNFRSF 各个成员对 NF-κB 和 MAPK 通路的激活。然而，cIAP1/2 在 RANK 信号传导中的参与仍然很大程度上未知。在这项研究中，我们揭示了 cIAP1/2 在 RANK 配体 (RANKL) 诱导的破骨细胞生成中的参与。在小鼠单核细胞系 Raw264.7 中过度表达 cIAP1 或 cIAP2 导致 RANKL 诱导的 NFATc1 mRNA 表达和破骨细胞生成受到显着抑制，而 NF-κB 和 MAPK 通路的激活几乎没有因这些过度表达而改变。通过特异性抑制剂 MV1 或 siRNA 介导的敲低来消除内源性 cIAP1/2，导致 RANKL 诱导的 NFATc1 表达和破骨细胞生成增强，而不影响 NF-κB 和 MAPK 通路的激活。综上所述，这些结果表明 cIAP1/2 通过抑制 NFATc1 mRNA 表达来负向调节破骨细胞生成，其方式与之前确定的 cIAP1/2 功能不同。
Receptor activator of nuclear factor κB (RANK) is a member of the tumor necrosis factor receptor superfamily (TNFRSF) and triggers osteoclastogenesis by inducing the expression of NFATc1 through the activation of the NF‐κB and MAPK pathways. Cellular inhibitors of apoptosis proteins 1 and 2 (cIAP1/2), which are ubiquitin E3 ligases, are involved in the activation of the NF‐κB and MAPK pathways by various members of the TNFRSF. However, the involvement of cIAP1/2 in RANK signaling has remained largely unknown. In this study, we reveal the involvement of cIAP1/2 in RANK ligand (RANKL)‐induced osteoclastogenesis. The over‐expression of cIAP1 or cIAP2 in the mouse monocytic cell line Raw264.7 resulted in the significant suppression of RANKL‐induced NFATc1 mRNA expression and osteoclastogenesis, whereas the activation of the NF‐κB and MAPK pathways was barely changed by these over‐expressions. The depletion of endogenous cIAP1/2 by their specific inhibitor MV1 or their siRNA‐mediated knockdown resulted in enhanced RANKL‐induced NFATc1 expression and osteoclastogenesis without affecting the activation of the NF‐κB and MAPK pathways. In combination, these results indicate that cIAP1/2 negatively regulate osteoclastogenesis by inhibiting NFATc1 mRNA expression in a manner that is distinct from the previously identified functions of cIAP1/2.