Jun N-terminal kinase in rheumatoid arthritis

Potential mechanisms of joint destruction in rheumatoid arthritis (RA) were examined by studying the regulation of mitogen-activated protein kinases a nd collagenase gene expression in fibroblast-like synoviocytes (FLS). The t hree main mitogen-activated protein kinase families [p38, Jun N-terminal ki nase (JNK), and extracellular signal-regulated kinases (ERKs)] were constit utively expressed in RA and osteoarthritis (OA) FLS. p38 and ERK1/2 were re adily phosphorylated in both RA and OA FLS after interleukin-1 (IL-1) stimu lation. JNK was phosphorylated in RA FLS but not OA FLS after IL-1 stimulat ion. Reverse transcription-polymerase chain reaction studies suggested that JNK2 is the major isoform of the JNK family expressed by FLS. Northern blo t analysis of collagenase gene expression demonstrated that RA FLS containe d significantly more collagenase mRNA than OA FLS after IL-1 stimulation. T he roles of JNK and p38 kinase were evaluated with the p38/JNK inhibitor SB 203580. Low concentrations of SB 203580 (1 mu M, a concentration that only inhibits p38) had no significant effect on IL-1-induced collagenase expres sion in RA FLS whereas 25 mu M (which inhibits p38, JNK2, and c-raf) blocke d collagenase mRNA accumulation. IL-1-stimulated AP-1 binding was also inhi bited by 25 mM SB 203580 in RA FLS. These studies suggest that OA and RA FL S have a different pattern of JNK phosphorylation, which might lead to enha nced collagenase gene expression in RA.