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Joint damage and inflammation in c-Jun N-terminal kinase 2 knockout mice with passive murine collagen-induced
Zuoning Han1, Lufen Chang, Yuji Yamanishi
1University of California San Diego School of Medicine, La Jolla 92093, USA.
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 knockout 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 CIA, 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.
Insights
Selective loss of c-Jun N-terminal kinase-2 (JNK-2) reduced joint destruction in arthritis models. However, complete inhibition of matrix metalloproteinase (MMP) expression and joint damage requires targeting both JNK-1 and JNK-2.
Area of Science:
- Immunology
- Molecular Biology
- Rheumatology
Background:
- Previous research indicated that inhibiting c-Jun N-terminal kinase (JNK) reduces joint destruction in rat adjuvant arthritis models.
- The role of specific JNK isoforms, particularly JNK-2, in inflammatory arthritis pathogenesis remains to be fully elucidated.
Purpose of the Study:
- To investigate the role of JNK-2 in inflammatory arthritis by examining joint destruction in JNK-2 knockout mice.
- To determine if the selective loss of JNK-2 function impacts the severity of collagen-induced arthritis (CIA).
Main Methods:
- Passive collagen-induced arthritis (CIA) was induced in JNK-2 knockout (Jnk2(-/-)) and wild-type mice.
- Arthritis severity was assessed using clinical scoring and histological analysis.
- Fibroblast-like synoviocytes (FLS) were isolated, and JNK protein expression, matrix metalloproteinase 13 (MMP-13) expression, and activator protein 1 (AP-1) binding activity were analyzed.
Main Results:
- JNK protein levels were significantly reduced in Jnk2(-/-) mice compared to wild-type controls.
- While clinical arthritis scores were slightly higher in Jnk2(-/-) mice, histological analysis revealed significantly less joint damage.
- Despite reduced joint destruction, AP-1 binding activity and MMP-13 expression were similar in both groups, suggesting a complex regulatory mechanism involving other JNK isoforms or cell types.
Conclusions:
- JNK-2 plays a critical role in matrix degradation but has a limited impact on synovial inflammation in arthritis.
- Targeting JNK-2 alone is insufficient to completely inhibit MMP expression and prevent joint destruction.
- Combined inhibition of both JNK-1 and JNK-2 may be necessary for complete suppression of MMPs and amelioration of joint damage in inflammatory arthritis.