The transcription factor Snail is involved in various biologic functions. We hypothesized that this molecule regulates tumor necrosis factor α (TNFα)-mediated synovial fibroblast activation in the rheumatoid joint. The aim of this study was to examine the role of Snail in the expression of cadherin-11 (Cad-11) and myofibroblast markers, interleukin-6 (IL-6) production, and the invasive ability of cells.
Synovium samples were obtained from patients with rheumatoid arthritis (RA) and from rats with collagen-induced arthritis (CIA). Synovial fibroblasts were treated with TNFα or a Wnt signaling inducer, and the joints of rats with CIA were injected with a TNFα antagonist. Modulation of Snail expression in the synovial fibroblasts and joints was performed by lentiviral vector-mediated transfer of complementary DNA or short hairpin RNA.
The expression of Snail and Cad-11 was higher in synovium and synovial fibroblasts from patients with RA compared with patients with osteoarthritis and was increased in rats with CIA. TNFα stimulation or activation of Wnt signaling up-regulated the expression of Snail, Cad-11, and α-smooth muscle actin (α-SMA) in synovial fibroblasts, and anti-TNFα therapy down-regulated the expression of Snail, Cad-11, and α-SMA in the joints of rats with CIA. Although synovial fibroblast transfectants in which Snail was overexpressed showed increased expression of Cad-11 and α-SMA and enhanced TNFα-mediated invasive capacity and IL-6 production, synovial fibroblast transfectants from rats with CIA in which Snail was silenced showed decreased expression and had the opposite effect on these functions. Normal joints in which Snail was overexpressed had hyperplastic synovium, with increased expression of Cad-11, α-SMA, and IL-6. Silencing Snail expression ameliorated arthritis, with reduced Cad-11 expression and reduced levels of extracellular matrix deposition in the joints of rats with CIA, whereas overexpression of Snail exacerbated arthritis, with increased Cad-11 expression and increased levels of extracellular matrix deposition.
Our results demonstrate that Snail regulates TNFα-mediated activation of synovial fibroblasts in the rheumatoid joint. These findings may contribute to the pharmacologic development of therapeutics targeting synovial fibroblasts in patients with RA.