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 inflammation and tissue destruction in rheumatoid arthritis (RA).In particular, c-Jun N-terminal kinase (JNK) is highly activated in RA fibroblast-like synoviocytes and synovium.However, defining the precise function of this kinase has 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 inflammatory arthritis.The novel JNK inhibitor SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one) completely blocked IL-1-induced accumulation of phospho-Jun and induction of c-Jun transcription in synoviocytes.Furthermore, AP-1 binding and collagenase mRNA accumulation were completely suppressed by SP600125.In contrast, complete inhibition of p38 had no effect, and ERK inhibition had only a modest effect.The essential role of JNK was confirmed in cultured synoviocytes from JNK1 knockout mice and JNK2 knockout mice, each of which had a partial defect in IL-1-induced AP-1 activation and collagenase-3 expression.Administration of SP600125 modestly decreased the rat paw swelling in rat adjuvant-induced arthritis.More striking was the near-complete inhibition of radiographic damage that was associated with decreased AP-1 activity and collagenase-3 gene expression.Therefore, JNK is a critical MAPK pathway for IL-1-induced collagenase gene expression in synoviocytes and in joint arthritis, indicating that JNK is an important therapeutic target for RA.