Role of cathepsin B in regulating migration and invasion of fibroblast‐like synoviocytes into inflamed tissue from patients with rheumatoid arthritis

Summary Cathepsin B ( CB ), an important proteinase that participates in joint destruction in rheumatoid arthritis ( RA ), exhibits higher expression in fibroblast‐like synoviocyte ( FLS ) of abnormal proliferative synovial tissues. Whether and how it affects the biological behaviours of RA‐FLS , such as migration and invasion, are poorly understood. In the present study, CB expression in synovial tissues of patients with RA and ostearthritis ( OA ) were measured by quantitative polymerase chain reaction (q PCR) and immunohistochemistry ( IHC ), respectively. Stable depletion of endogenous CB was achieved by small interfering RNA (si RNA) transfection, and decrease of CB activity was acquired by using its specific inhibitor ( C A074 M e). The effects of C A074 M e and RNA interference ( RNAi) treatments on proliferation, migration, invasion, matrix metalloproteinase ( MMP) ‐2/‐9 expression, focal adhesion kinase ( FAK ) activation, and mitogen‐activated protein kinases ( MAPK s) phosphorylation of FLS were analysed. In RA synovial tissues, CB was expressed at elevated levels compared with OA synovial tissues. C A074 M e could inhibit invasion of FLS obtained from RA patients in an ex‐vivo invasion model. C A074 M e and si RNA treatments suppressed the migration and invasion of FLS , reduced the activity, expression and m RNA level of MMP ‐2, restrained the activation of FAK and reduced the expression of F ‐actin. Moreover, CA 074Me decreased the phosphorylation of P 38 MAPK and c‐Jun N‐terminal kinase ( JNK) in FLS , while si CB treatment reduced the phosphorylation of P 38 but not JNK . CB substantially contributes to the invasive phenotype of FLS that leads to joint destruction in RA . This proteinase may show promise as a therapeutic target in inflammatory arthritis.