Background Rheumatoid arthritis (RA) is characterized by the aggressive synovial expansion due to angiogenesis and subsequent destruction of the underlying cartilage and bone. Synovial cells produce inflammatory mediators, proteases, and angiogenic growth factors such as prostaglandin (PG) E2, IL-6, matrix metalloproteinase-3 (MMP-3) and vascular endothelial growth factor (VEGF). We previously demonstrated that blocking hepatocyte growth factor (HGF) receptor, c-Met signal by HGF antagonist, NK4 inhibited arthritis in RA model of SKG mice.
Objectives In the present study we examined the role of c-Met signal for the production of PGE2, IL-6, MMP-3 and VEGF by synovial cells.
Methods HGF or c-Met expressions in synovial tissues were examined by immunohistochemistry using either anti-human HGF Ab or anti-human c-Met Ab. Human MH7A synovial cell line was established by transfection with SV40 T antigen to synovial cells which was isolated from knee joint intraarticular soft tissue of RA patients. PGE2, IL-6, MMP-3 and VEGF productions from MH7A cells were determined by ELISA. Extracellular signal-regulated kinase (ERK) 1/2 and AKT phosphorylation was determined by Western blot analysis. The effect of MEK1/2 inhibitor, PI3 kinase inhibitor or c-Met kinase inhibitor was examined by the treatment of the cells with PD98059, LY294002 or SU11274, respectively.
Results HGF and c-Met expressions in RA synovium were increased comparing to those in osteoarthritis synovium, suggesting the increased c-Met signal in RA synovial cells. We also detected c-Met expressions in MH7A. Blocking c-Met signal by SU11274 or NK4 inhibited ERK1/2 and AKT phosphorylation by HGF-stimulated MH7A cells. Both MEK and PI3K inhibitor suppressed PGE2, IL-6, MMP-3 and VEGF production. These results indicate that positive c-Met-MEK-ERK and c-Met-PI3K-AKT signal pathways are involved in MH7A cells. Although blocking c-Met signal by SU11274 or NK4 inhibited the production of MMP-3 and VEGF, however, it enhanced the production of PGE2 and IL-6 by MH7A cells.
Conclusions These results indicate that positive c-Met-MEK-ERK and c-Met-PI3K-AKT signal pathways are involved in MMP-3 and VEGF production by MH7A cells. Although positive MEK-ERK and PI3K-AKT signal pathways are involved, negative c-Met signals independent to MEK-ERK and PI3K-AKT signal pathways are involved in PGE2 and IL-6 production. Blocking c-Met signal may be useful for the inhibition of angiogenesis and cartilage and bone destruction by the inhibition of VEGF and MMP-3 production, while it enhances PGE2 and IL-6 production by synovial cells in RA.
Arthritis. Res. Ther. 22 (2013) R75.
Disclosure of Interest None declared
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