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Vol. 291, Issue 1, 124-130, October 1999
Division of Rheumatology, Allergy, and Immunology, University of
California at San Diego School of Medicine (Z.H., D.L.B., K.R.A.,
G.S.F.) , La Jolla, California; and Department of Inflammation, Signal
Pharmaceuticals, Inc. (B.B., A.M.M.), San Diego, California
Potential mechanisms of joint destruction in rheumatoid arthritis (RA)
were examined by studying the regulation of mitogen-activated protein kinases and collagenase gene expression in
fibroblast-like synoviocytes (FLS). The three main mitogen-activated
protein kinase families [p38, Jun N-terminal kinase (JNK), and
extracellular signal-regulated kinases (ERKs)] were constitutively
expressed in RA and osteoarthritis (OA) FLS. p38 and ERK1/2 were
readily phosphorylated in both RA and OA FLS after interleukin-1
(IL-1) stimulation. JNK was phosphorylated in RA FLS but not OA
FLS after IL-1 stimulation. Reverse transcription-polymerase chain
reaction studies suggested that JNK2 is the major isoform of the
JNK family expressed by FLS. Northern blot analysis of collagenase gene
expression demonstrated that RA FLS contained significantly more
collagenase mRNA than OA FLS after IL-1 stimulation. The roles of JNK
and p38 kinase were evaluated with the p38/JNK inhibitor SB 203580. Low
concentrations of SB 203580 (1 µM, a concentration that only inhibits
p38) had no significant effect on IL-1-induced collagenase expression
in RA FLS whereas 25 µM (which inhibits p38, JNK2, and c-raf) blocked
collagenase mRNA accumulation. IL-1-stimulated AP-1 binding was also
inhibited by 25 µM SB 203580 in RA FLS. These studies suggest that OA
and RA FLS have a different pattern of JNK phosphorylation, which might
lead to enhanced collagenase gene expression in RA.
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