The IκB kinase (IKK) inhibitor, NEMO-binding domain peptide, blocks osteoclastogenesis and bone erosion in inflammatory arthritis
The IκB kinase (IKK) inhibitor, NEMO-binding domain peptide, blocks osteoclastogenesis and bone erosion in inflammatory arthritis
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DOI：
10.1074/jbc.c400258200
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发表时间：
2004-09-03
影响因子：
4.8
通讯作者：
Abu-Amer, Y
中科院分区：
文献类型：
--
作者：
Dai, S;Hirayama, T;Abu-Amer, Y
核因子-kappaB的激活导致调节炎症和破骨细胞反应的大量基因的表达。这一过程是通过诱导IkappaB激酶(IKK)复合体的诱导来实现的，该复合体使IkappaB磷酸化，并导致其从NF-kappaB复合体中解离，从而允许NF-kappaB的激活。IKK复合体主要包括IKKalpha、IKKbeta和调节激酶IKKGamma，也称为Nemo。Nemo通过与IKKalpha和IKKβ的羧基末端区域结合来调节IKK复合体的活性，称为Nemo结合结构域(NBD)。在这方面，一种细胞通透性的NBD多肽已被证明可以阻断NEMO与IKK复合体的联系，并抑制NF-kappaB的激活。鉴于细胞因子诱导的核因子-kappaB在破骨细胞生成和炎症性骨丢失中的关键作用，我们推测细胞通透性TAT-NBD多肽可能阻碍了炎性关节炎的破骨细胞生成和骨侵蚀。使用NBD多肽，我们发现，野生型，而不是突变型，阻断了IKK的激活，降低了细胞因子诱导的核因子-kappaB的启动子和DNA结合活性，并抑制了破骨细胞前体细胞因子诱导的破骨细胞形成。与体内核因子-kappaB在骨炎症反应中的关键作用一致，在诱导炎性关节炎之前，野生型TAT-NBD有效地阻断了体内破骨细胞的形成，抑制了局部骨侵蚀，并改善了关节炎小鼠关节的炎症反应。突变的NBD多肽不能发挥这些功能。这些结果提供了强有力的证据表明，IKKS是细胞因子诱导的破骨细胞形成和炎症性关节炎的有效调节因子。更重要的是，用IKK复合体阻断NEMO组装是避免炎性骨溶解的可行策略。
Activation of NF-kappaB leads to expression of ample genes that regulate inflammatory and osteoclastogenic responses. The process is facilitated by induction of IkappaB kinase (IKK) complex that phosphorylates IkappaB and leads to its dissociation from the NF-kappaB complex, thus permitting activation of NF-kappaB. The IKK complex contains primarily IKKalpha,IKKbeta, and the regulatory kinase IKKgamma, also known as NEMO. NEMO regulates the IKK complex activity through its binding to carboxyl-terminal region of IKKalpha and IKKbeta, termed NEMO-binding domain (NBD). In this regard, a cell-permeable NBD peptide has been shown to block association of NEMO with the IKK complex and inhibit activation of NF-kappaB. Given the pivotal role of cytokine-induced NF-kappaB in osteoclastogenesis and inflammatory bone loss, we deduced that cell-permeable TAT-NBD peptide may hinder osteoclastogenesis and bone erosion in inflammatory arthritis. Using NBD peptides, we show that wild type, but not mutant, NBD blocks IKK activation and reduces cytokine-induced promoter and DNA binding activities of NF-kappaB and inhibits cytokine-induced osteoclast formation by osteoclast precursors. Consistent with the key role of NF-kappaB in osteoinflammatory responses in vivo, wild type TAT-NBD administered into mice prior to induction of inflammatory arthritis efficiently block in vivo osteoclastogenesis, inhibits focal bone erosion, and ameliorates inflammatory responses in the joints of arthritic mice. The mutant NBD peptide fails to exert these functions. These results provide strong evidence that IKKs are potent regulators of cytokine-induced osteoclastogenesis and inflammatory arthritis. More importantly, blockade of NEMO assembly with the IKK complex is a viable strategy to avert inflammatory osteolysis.