Joint damage and inflammation in c-Jun N-terminal kinase 2 knockout mice with passive murine collagen-induced arthritis

被引:107
作者
Han, ZN [1 ]
Chang, LF [1 ]
Yamanishi, Y [1 ]
Karin, M [1 ]
Firestein, GS [1 ]
机构
[1] Univ Calif San Diego, Sch Med, Div Rheumatol Allergy & Immunol, La Jolla, CA 92093 USA
来源
ARTHRITIS AND RHEUMATISM | 2002年 / 46卷 / 03期
关键词
D O I
10.1002/art.10104
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:818 / 823
页数:6
相关论文
共 18 条
[1]   Integration of the NF-κB and mitogen-activated protein kinase/AP-1 pathways at the collagenase-1 promoter:: Divergence of IL-1 and TNF-dependent signal transduction in rabbit primary synovial fibroblasts [J].
Barchowsky, A ;
Frleta, D ;
Vincenti, MP .
CYTOKINE, 2000, 12 (10) :1469-1479
[2]  
Chabaud M, 1999, ARTHRITIS RHEUM-US, V42, P963, DOI 10.1002/1529-0131(199905)42:5<963::AID-ANR15>3.0.CO
[3]  
2-E
[4]   JNK is required for effector T-cell function but not for T-cell activation [J].
Dong, C ;
Yang, DD ;
Tournier, C ;
Whitmarsh, AJ ;
Xu, J ;
Davis, RJ ;
Flavell, RA .
NATURE, 2000, 405 (6782) :91-94
[5]   Isoforms of jun kinase are differentially expressed and activated in human monocyte/macrophage (THP-1) cells [J].
Dreskin, SC ;
Thomas, GW ;
Dale, SN ;
Heasley, LE .
JOURNAL OF IMMUNOLOGY, 2001, 166 (09) :5646-5653
[6]  
Firestein GS, 1999, ARTHRITIS RHEUM-US, V42, P609, DOI 10.1002/1529-0131(199904)42:4<609::AID-ANR3>3.0.CO
[7]  
2-I
[8]  
FIRESTEIN GS, 1998, SCI AM MED
[9]   Selective interaction of JNK protein kinase isoforms with transcription factors [J].
Gupta, S ;
Barrett, T ;
Whitmarsh, AJ ;
Cavanagh, J ;
Sluss, HK ;
Derijard, B ;
Davis, RJ .
EMBO JOURNAL, 1996, 15 (11) :2760-2770
[10]  
Han ZN, 1999, J PHARMACOL EXP THER, V291, P124