Regulation of fibronectin and metalloproteinase expression by Wnt signaling in rheumatoid arthritis synoviocytes

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Abstract
Objective: The enhanced release of extracellular matrix proteins by fibroblast‐like synoviocytes (FLS) from rheumatoid arthritis (RA) patients is suggestive of joint remodeling. Because Wnt proteins play a critical role in joint development, we investigated whether up‐regulated Wnt signaling plays a role in the enhanced synthesis of extracellular matrix proteins. The purpose of the present experiments was to determine the role of Wnt‐1–like molecules in the expression of matrix proteins by RA FLS and to ascertain the effects of Wnt antagonists on RA FLS function and survival.Methods: Transfection with a reporter plasmid (TOPflash) was performed to assess whether Wnt signaling is active in RA FLS. Wnt signaling was up‐regulated in normal FLS by transfection with a Wnt‐1 expression plasmid and was down‐regulated in RA FLS by transfection with dominant‐negative lymphoid enhancer factor 1 (LEF‐1)/T cell factor 4 (TCF‐4) and secreted Frizzled receptor protein 1 (sFRP‐1) expression plasmids. Recombinant sFRP‐1 and anti–Wnt‐1 antibody were also administered to RA FLS to block Wnt signaling.Results: RA FLS had constitutive activation of the canonical Wnt signaling pathway. Transfection of normal FLS with a Wnt‐1 expression vector enhanced not only fibronectin, but also pro–matrix metalloproteinase 3 (proMMP‐3) expression. In a complementary manner, interference with Wnt signaling using anti–Wnt‐1 antibody, the Wnt antagonist sFRP‐1, or dominant‐negative vectors that inhibited the transcription factors TCF‐4/LEF‐1 blocked the expression of fibronectin by RA FLS and reduced cell survival. Anti–Wnt‐1 antibody and sFRP‐1 also blocked the expression of proMMP‐3.Conclusion: Our results indicate that the canonical Wnt pathway regulates fibronectin and metalloproteinase expression in RA FLS.

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