Intra-articular administration of IκBα kinase inhibitor suppresses mouse knee osteoarthritis via downregulation of the NF-κB/HIF-2α axis.
Intra-articular administration of IκBα kinase inhibitor suppresses mouse knee osteoarthritis via downregulation of the NF-κB/HIF-2α axis.
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DOI：
10.1038/s41598-018-34830-9
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发表时间：
2018-11-07
影响因子：
4.6
通讯作者：
Saito T
中科院分区：
文献类型：
--
作者：
Murahashi Y;Yano F;Kobayashi H;Makii Y;Iba K;Yamashita T;Tanaka S;Saito T
核因子-κB信号的激活通过转录诱导HIF-2α和分解代谢酶促进骨关节炎的发生。本研究旨在检测抑制I-κB-α激酶(IKK)是否可以抑制手术诱导的小鼠膝关节骨关节炎的发展。我们用BMS-345541(4(2‘-氨乙基)氨基-1，8-二甲基咪唑(1，2-a)喹恶啉)作为IKK亚基的选择性抑制剂。切除小鼠膝部内侧副韧带和内侧半月板，形成骨关节炎模型。然后给小鼠关节腔内注射BMS-345541(50 NM到500 µM)或赋形剂，每周3次，共8周。我们发现关节腔内注射500 NM和5 微米BMS-345541显著抑制了骨性关节炎的发展。在BMS-345541处理的软骨中，IκBα的磷酸化水平降低，HIF-2α、MMP13和Adams 5的表达降低。在人关节软骨细胞中，IL-1β增强的HIF-2α和分解代谢因子的表达被BMS-345541剂量依赖性地降低。我们的结论是，关节腔内注射一定浓度的BMS-345541可能通过下调NF-κB-HIF-2α轴的信号转导来抑制OA的发展。
Activation of NF-κB signaling promotes osteoarthritis (OA) through the transcriptional induction of Hif-2α and catabolic enzymes. This study sought to examine whether inhibiting IκBα kinase (IKK) could suppress the development of surgically-induced OA of the knee in a mouse model. We employed BMS-345541 (4(2′-aminoethyl) amino-1, 8-dimethylimidazo (1,2-a) quinoxaline) as a selective inhibitor of the subunits of IKK. OA was created by resecting the medial collateral ligament and the medial meniscus in the knees of mice. The mice were then treated with an intra-articular injection of BMS-345541 (50 nM to 500 µM) or vehicle three times a week for 8 weeks. We found that the intra-articular administration of 500 nM and 5 µM BMS-345541 significantly suppressed OA development. In the BMS-345541-treated cartilage, there was a decrease in the phosphorylation of IκBα and the expression of Hif-2α, Mmp13, and Adamts5. In human articular chondrocytes, the IL-1β-enhanced expression of Hif-2α and catabolic factors were decreased by BMS-345541 treatment in dose-dependent manner. We conclude that the intra-articular administration of BMS-345541 at some concentrations may suppress the development of OA by downregulating signaling through the NF-κB–Hif-2α axis.
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影响因子：
16.6
作者：
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通讯作者：
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通讯作者：
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影响因子：
11.5
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通讯作者：
Richmond, A
影响因子：
4.8
作者：
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通讯作者：
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影响因子：
4.3
作者：
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通讯作者：
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