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

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Abstract
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.

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