Regulation of inflammatory arthritis by the upstream kinase mitogen activated protein kinase kinase 7 in the c-Jun N-terminal kinase pathway.
Regulation of inflammatory arthritis by the upstream kinase mitogen activated protein kinase kinase 7 in the c-Jun N-terminal kinase pathway.
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DOI：
10.1186/ar3750
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发表时间：
2012-02-21
影响因子：
4.9
通讯作者：
Firestein GS
中科院分区：
文献类型：
--
作者：
Lee SI;Boyle DL;Berdeja A;Firestein GS
C-Jun氨基末端激酶(JNK)是类风湿关节炎(RA)中基质金属蛋白酶(MMPs)和细胞因子产生的关键调节因子，JNK缺乏对关节炎动物模型小鼠有明显的保护作用。细胞因子诱导的JNK激活严格依赖于成纤维样滑膜细胞中的丝裂原活化蛋白激酶7(MKK7)。因此，我们评估了使用反义寡核苷酸(ASO)靶向MKK7是否会降低K/BxN血清转移性关节炎的JNK活性和严重程度。给正常C57BL/6小鼠静脉注射MKK7和对照ASO的3个2‘-O-甲氧乙基嵌合ASO。被动K/BxN模型第8天至第10天分别注射PBS、对照ASO或MKK7 ASO。采用半定量评分系统对踝关节组织学进行评价。定量聚合酶链式反应和Western印迹分析检测MKK7和JNK信号通路的表达。在3天内，MKK7 ASO可使正常小鼠踝关节MKK7的mRNA和蛋白水平降低约40%。对照ASO对MKK7的表达无影响，MKK7 ASO对MKK3、MKK4、MKK6无影响。与对照组相比，注射MKK7 ASO的小鼠关节炎严重程度显著减轻(P<；0.01)。MKK7 ASO治疗的小鼠滑膜炎症、骨侵蚀和软骨损伤的组织学证据减少(P<；0.01)。MKK7缺乏降低了脚踝提取液中磷酸化JNK和磷酸化c-JUN(P<；0.05)，但不降低磷酸化MKK4。MKK7ASO组大鼠踝关节组织中IL-1β(IL-1β)、MMP3和MMP13基因表达明显降低(P<0.01)。在小鼠关节炎模型中，MKK7在JNK通路中起着关键的调节作用。在治疗滑膜炎时，靶向MKK7而不是JNK可以提供部位和事件特异性。
The c-Jun N-terminal kinase (JNK) is a key regulator of matrix metalloproteinase (MMP) and cytokine production in rheumatoid arthritis (RA) and JNK deficiency markedly protects mice in animal models of arthritis. Cytokine-induced JNK activation is strictly dependent on the mitogen-activated protein kinase kinase 7 (MKK7) in fibroblast-like synoviocytes (FLS). Therefore, we evaluated whether targeting MKK7 using anti-sense oligonucleotides (ASO) would decrease JNK activation and severity in K/BxN serum transfer arthritis. Three 2'-O-methoxyethyl chimeric ASOs for MKK7 and control ASO were injected intravenously in normal C57BL/6 mice. PBS, control ASO or MKK7 ASO was injected from Day -8 to Day 10 in the passive K/BxN model. Ankle histology was evaluated using a semi-quantitative scoring system. Expression of MKK7 and JNK pathways was evaluated by quantitative PCR and Western blot analysis. MKK7 ASO decreased MKK7 mRNA and protein levels in ankles by about 40% in normal mice within three days. There was no effect of control ASO on MKK7 expression and MKK7 ASO did not affect MKK3, MKK4 or MKK6. Mice injected with MKK7 ASO had significantly less severe arthritis compared with control ASO (P < 0.01). Histologic evidence of synovial inflammation, bone erosion and cartilage damage was reduced in MKK7 ASO-treated mice (P < 0.01). MKK7 deficiency decreased phospho-JNK and phospho-c-Jun in ankle extracts (P < 0.05), but not phospho-MKK4. Interleukin-1beta (IL-1β), MMP3 and MMP13 gene expression in ankle joints were decreased by MKK7 ASO (P < 0.01). MKK7 plays a critical regulatory role in the JNK pathway in a murine model of arthritis. Targeting MKK7 rather than JNK could provide site and event specificity when treating synovitis.
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