Joint damage and inflammation in c-Jun N-terminal kinase 2 knockout mice with passive murine collagen-induced arthritis
Joint damage and inflammation in c-Jun N-terminal kinase 2 knockout mice with passive murine collagen-induced arthritis
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DOI：
10.1002/art.10104
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发表时间：
2002-03-01
影响因子：
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通讯作者：
Firestein, GS
中科院分区：
文献类型：
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作者：
Han, ZN;Chang, LF;Firestein, GS
Objective.先前的研究表明，抑制c-Jun N-末端激酶（JNK）减少大鼠佐剂性关节炎模型中的关节破坏。本研究旨在研究JNK-2功能的选择性丧失是否会降低JNK-2基因敲除小鼠的关节破坏，以确定该亚型在炎症性关节炎中的作用。通过施用抗II型胶原抗体在JNK 2（-/-）和野生型小鼠中诱导被动胶原诱导的关节炎（CIA）。每天使用半定量临床评分系统评估关节炎。从JNK 2（-/-）和野生型小鼠制备成纤维细胞样滑膜细胞（FLS），并通过Western印迹分析测定JNK蛋白表达。采用北方印迹法检测细胞基质金属蛋白酶13（MMP-13）的表达，电迁移率改变法（EMSA）检测细胞激活蛋白1（AP-1）的结合活性。JNK 2（-/-）CIA小鼠JNK蛋白表达水平为野生型CIA小鼠的22%（P < 0.001），且以46 kd亚型为主。令人惊讶的是，临床关节炎在Jnk 2（-/-）小鼠中稍微更严重。滑膜炎症的组织学评分无显著差异。然而，来自Jnk 2（-/-）小鼠的番红O染色切片表现出显著更少的关节损伤。尽管CU的Jnk 2（-/-）小鼠的关节破坏减少，但总关节提取物的EMSA和北方印迹分析显示Jnk 2（-/-）和野生型小鼠中AP-1结合和MMP-13表达水平相似。AP-1活性和MMP表达之间缺乏相关性可能是因为关节中非FLS细胞比FLS细胞表达更多的JNK-1。JNK-2是基质降解的决定因素，但对关节炎的炎症影响不大。MMP表达的完全抑制和关节破坏可能需要联合JNK-1和JNK-2抑制。
Objective. Previous studies have demonstrated that inhibition of c-Jun N-terminal kinase (JNK) decreases joint destruction in the rat adjuvant arthritis model. The present study was undertaken to investigate whether selective loss of JNK-2 function decreases joint destruction in JNK-2 knock-out mice, in order to determine the role of this isoform in inflammatory arthritis.Methods. Passive collagen-induced arthritis (CIA) was induced in Jnk2(-/-) and wild-type mice by administering anti-type II collagen antibodies. Arthritis was assessed daily using a semiquantitative clinical scoring system. Fibroblast-like synoviocytes (FLS) were prepared from Jnk2(-/-) and wild-type mice, and JNK protein expression was determined by Western blot analysis. Matrix metalloproteinase 13 (MMP-13) expression was determined by Northern blot analysis, and activator protein 1 (AP-1) binding activity by electromobility shift assay (EMSA).Results. The JNK protein level in Jnk2(-/-) mice with CIA was 22% of that in wild-type mice with CIA, (P < 0.001), and mainly the 46-kd isoform was expressed in the former group. Surprisingly, clinical arthritis was slightly more severe in the Jnk2(-/-) mice. Histologic scores for synovial inflammation were not significantly different. However, Safranin O-stained sections from the Jnk2(-/-) mice exhibited significantly less joint damage. Although joint destruction was decreased in Jnk2(-/-) mice with CU, EMSA and Northern blot analysis of total joint extracts revealed similar levels of AP-1 binding and MMP-13 expression in Jnk2(-/-) and wild-type mice. The lack of correlation with AP-1 activity and MMP expression was probably because non-FLS cells in the joint may express more JNK-1 than do FLS.Conclusion. JNK-2 is a determinant of matrix degradation, but it has little effect on inflammation in arthritis. Complete inhibition of MMP expression and joint destruction will likely require combined JNK-1 and JNK-2 inhibition.