C-Jun N-terminal kinase is required for metalloproteinase expression, and joint destruction in inflammatory arthritis

Mitogen-activated protein kinase (MAPK) cascades are involved in inflammati on and tissue destruction in rheumatoid arthritis (RA). In particular, c-Ju n N-terminal kinase (JNK) is highly activated in RA fibroblast-like synovio cytes and synovium. However, defining the precise function of this kinase h as been difficult because a selective JNK inhibitor has not been available. We now report the use of a novel selective JNK inhibitor and JNK knockout mice to determine the function of JNK in synoviocyte biology and inflammato ry arthritis. The novel JNK inhibitor SP600125 (anthra[1,9-cd]pyrazol-6(2H) -one) completely blocked IL-1-induced accumulation of phospho-Jun and induc tion of c-Jun transcription in synoviocytes. Furthermore, AP-1 binding and collagenase mRNA accumulation were completely suppressed by SP600125. In co ntrast, complete inhibition of p38 had no effect, and ERK inhibition had on ly a modest effect. The essential role of JNK was confirmed in cultured syn oviocytes from JNK1 knockout mice and JNK2 knockout mice, each of which had a partial defect in TL-1-induced AP-1 activation and collagenase-3 express ion. Administration of SP600125 modestly decreased the rat paw swelling in rat adjuvant-induced arthritis. More striking was the near-complete inhibit ion of radiographic damage that was associated with decreased AP-1 activity and collagenase-3 gene expression. Therefore, JNK is a critical MAPK pathw ay for IL-1-induced collagenase gene expression in synoviocytes and in join t arthritis, indicating that JNK is an important therapeutic target for RA.