Impediment of NEMO oligomerization inhibits osteoclastogenesis and osteolysis.
Impediment of NEMO oligomerization inhibits osteoclastogenesis and osteolysis.
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DOI：
10.1002/jcb.22364
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发表时间：
2009-12-15
影响因子：
4
通讯作者：
Abu-Amer, Yousef
中科院分区：
文献类型：
--
作者：
Darwech, Isra;Otero, Jesse;Alhawagri, Muhammad;Dai, Simon;Abu-Amer, Yousef
转录因子NF-κB对破骨细胞的形成至关重要，被认为是类风湿关节炎和炎症性骨溶解的免疫调节剂。NF-κB亚基的活化受上游i -κB激酶（IKK）复合物调控，IKK复合物包含IKKα、IKKβ和IKKγ；后者也被称为NF-κB本质调制器（NEMO）。IKKα和IKKβ在骨骼发育和炎症性骨溶解中的作用已被描述，而NEMO在这种情况下的作用知之甚少。通常，RANK配体（RANKL）或TNF诱导的信号通过卷曲-卷曲-2 （CC2）和亮氨酸拉链（LZ）基序促使NEMO单体低聚。这一步骤有助于与IKKs结合并进一步传递信号转导。鉴于NF-κB在破骨细胞形成中的核心作用，我们想知道NEMO是否对破骨细胞形成至关重要，以及NEMO寡聚化的中断是否会阻碍体外和体内破骨细胞的分化。利用重叠CC2和LZ基序的细胞渗透性短肽，我们发现这些肽特异性地结合NEMO单体，阻止三聚体的形成，并使NEMO单体容易被泛素介导的降解。此外，CC2和LZ肽可减弱RANKL-和tnf诱导的骨髓源性破骨细胞前体（OCPs）中的NF-κ b信号。更重要的是，这些肽在体外有效地抑制破骨细胞的形成，并在小鼠中阻止rankl诱导的骨溶解。为了进一步确定其在破骨细胞发生中的作用，我们能够使用NEMO siRNA敲低方法阻断破骨细胞发生。总的来说，我们的数据表明，阻碍NEMO寡聚化会破坏NEMO单体的稳定性，抑制NF-κB的激活，阻碍破骨细胞的发生，阻止炎症性骨溶解。因此，NEMO是抗溶骨干预的一个有希望的靶点。
The transcription factor NF-κB is essential for osteoclastogenesis and is considered an immune-modulator of rheumatoid arthritis and inflammatory osteolysis. Activation of NF-κB subunits is regulated by the upstream IκB kinase (IKK) complex which contains IKKα, IKKβ, and IKKγ; the latter also known as NF-κB essential modulator (NEMO). The role of IKKα and IKKβ in the skeletal development and inflammatory osteolysis has been described, whereas little is known regarding the role of NEMO in this setting. Typically, signals induced by RANK ligand (RANKL) or TNF prompt oligomerization of NEMO monomers through the coiled-coil-2 (CC2) and leucine zipper (LZ) motifs. This step facilitates binding to IKKs and further relaying signal transduction. Given the central role of NF-κB in osteoclastogenesis, we asked whether NEMO is essential for osteoclastogenesis and whether interruption of NEMO oligomerization impedes osteoclast differentiation in vitro and in vivo. Using cell-permeable short peptides overlapping the CC2 and LZ motifs we show that these peptides specifically bind to NEMO monomers, prevent trimer formation, and render NEMO monomers susceptible for ubiquitin-mediated degradation. Further, CC2 and LZ peptides attenuate RANKL- and TNF-induced NF-κB signaling in bone marrow-derived osteoclast precursors (OCPs). More importantly, these peptides potently inhibit osteoclastogenesis, in vitro, and arrest RANKL-induced osteolysis, in mice. To further ascertain its role in osteoclastogenesis, we were able to block osteoclastogenesis using NEMO siRNA knockdown approach. Collectively, our data establish that obstruction of NEMO oligomerization destabilizes NEMO monomers, inhibits NF-κB activation, impedes osteoclastogenesis and arrests inflammatory osteolysis. Thus, NEMO presents itself as a promising target for anti-osteolytic intervention.
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DOI：
10.1084/jem.20042081
发表时间：
2005-05-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ruocco MG;Maeda S;Park JM;Lawrence T;Hsu LC;Cao Y;Schett G;Wagner EF;Karin M
通讯作者：
Karin M
影响因子：
64.8
作者：
Lawrence, T;Bebien, M;Karin, M
通讯作者：
Karin, M
影响因子：
4.8
作者：
Chaisson, ML;Branstetter, DG;Dougall, WC
通讯作者：
Dougall, WC
影响因子：
4.8
作者：
Agou, F;Courtois, G;Véron, M
通讯作者：
Véron, M
影响因子：
64.5
作者：
Regnier, CH;Song, HY;Rothe, M
通讯作者：
Rothe, M