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- Title
Activation of dickkopf-1 and focal adhesion kinase pathway by tumour necrosis factor α induces enhanced migration of fibroblast-like synoviocytes in rheumatoid arthritis.
- Authors
Jung-Yoon Choe; Ji Hun Kim; Ki-Yeun Park; Chang-Hyuk Choi; Seong-Kyu Kim
- Abstract
Objective. The objective of this study was to investigate the roles of dickkopf-1 (DKK-1) and integrin-related focal adhesion kinase (FAK) by TNF-α on the migration of fibroblast-like synoviocytes (FLSs) in RA. Methods. Wound scratch assays were performed to assess FLS migration. Western blotting was used to measure the levels of DKK-1, Wnt signalling molecules and FAK signalling molecules. Quantitative realtime PCR was used to measure the expression levels of DKK-1, integrin αv, laminin, fibronectin, E-cadherin, MMP-8 and MMP-13. The concentrations of DKK-1, TNF-α and GSK-3β were measured by ELISA. Genetic silencing of TNF-α was achieved by the transfection of small interfering RNA into cells. Results. Migrating RA FLSs exhibited higher levels of DKK-1 and TNF-α expression compared with those in OA FLSs and/or stationary RA FLSs. Moreover, migrating FLSs exhibited significantly higher levels of FAK, p-JNK, paxillin and cdc42 expression, whereas the level of cytosolic β-catenin was lower. WAY-262611, Wnt pathway agonist via inhibition of DKK-1, markedly inhibited cell migration of RA FLSs through the accumulation of cytosolic β-catenin and suppression of FAK-related signalling pathways. TNF-α treatment to RA FLSs up-regulated expression of DKK-1, integrin αv, fibronectin, laminin and MMP-13. TNF-α stimulation also suppressed cytosolic β-catenin and E-cadherin expression in a time-dependent manner. Moreover, TNF-α small interfering RNA-transfected migrating FLSs exhibited decreased activation of integrin-related FAK, paxillin, p-JNK and cdc42 signalling pathways. Conclusion. This study demonstrates that the activation of DKK-1 and the integrin-related FAK signalling pathway stimulated by TNF-α induces the dissociation of β-catenin/E-cadherin, thus promoting RA FLS migration.
- Subjects
CELL culture; CELLULAR signal transduction; ENZYME-linked immunosorbent assay; POLYMERASE chain reaction; RESEARCH funding; RHEUMATOID arthritis; SYNOVIAL membranes; TRANSFERASES; TUMOR necrosis factors; WESTERN immunoblotting; DATA analysis software; DESCRIPTIVE statistics; MANN Whitney U Test
- Publication
Rheumatology, 2016, Vol 55, Issue 5, p928
- ISSN
1462-0324
- Publication type
Article
- DOI
10.1093/rheumatology/kev422