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AB0139 Activation of Dickkopf-1 and Focal Adhesion Kinase Pathway by Tumor Necrosis Factor-Alpha Enhanced Migration of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis
  1. S.-K. Kim,
  2. J.-Y. Choe
  1. Catholic University of Daegu School of Medicine, Daegu, Korea, Republic Of

Abstract

Background The migration of fibroblast-like synoviocytes (FLS) has been recognized as a unique feature in rheumatoid arthritis (RA).

Objectives This study investigated the role of dickkopf-1 (DKK-1) and integrin-related focal adhesion kinase (FAK) on the cell migration of fibroblast-like synoviocytes (FLS) through the regulation of β-catenin in RA.

Methods The activation of migration were preformed by wound scratching assays. The expression of Wnt/β-catenin and FAK signaling molecules was determined by western blot. Expression of integrin αv, laminin, fibronectin, E-cadherin, integrins, MMP-8, and MMP-13 was measured by real-time quantitative RT-PCR. The DKK-1 morphology was observed by fluorescence microscopy. The inhibitory effects of TNF-α were employed by small interfering RNA transfection into cells.

Results More enhanced DKK-1 and TNF-α expression in migrating RA FLS were noted than those in OA FLS and/or stationary FLS. Migrating FLS induced FAK, p-JNK, paxillin, and cdc42 expression, but attenuated cytosolic β-catenin expression. WAY-262611 markedly inhibited cell migration in RA FLS through accumulation of cytosolic β-catenin and suppression of FAK-related signaling pathway. TNF-α enhanced DKK-1, integrin αv, fibronectin, laminin, and MMP-13 expression, which were markedly reduced by WAY-262611 treated with FLS. Increased expression of integrin-related FAK and its downstream molecules such as paxillin, JNK, and cdc42 in migrating FLS was suppressed by blocking TNF-α using RLS trasnfected with siRNA TNF-α. TNF-α suppressed cytosolic β-catenin and E-cadherin expression in time-dependent manner.

Conclusions This study demonstrated that enhanced expression of DKK-1 and activation of integrin-related FAK signal pathway stimulated by TNF-α induced dissociation of β-catenin and E-cadherin, then resulting in promotion of RA FLS migration.

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Disclosure of Interest None declared

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