Session Title: Rheumatoid Arthritis - Animal Models
Session Type: Abstract Submissions (ACR)
Background/Purpose: Transcription factor Snail plays active roles in various biological functions and is involved in many disease states. We hypothesized that this molecule regulates TNF-α-mediated activation of rheumatoid synovial fibroblasts (SF), and examined its roles in expression of Cadherin-11 (Cad-11) and α-smooth muscle actin (α-SMA, a myofibroblast marker), invasive ability and IL-6 production.
Methods: Synovial tissues were obtained from patients with rheumatoid arthritis (RA), a diagnosis according to 2010 RA classification criteria, and an experimental arthritis model of collagen-induced arthritis (CIA) in rats. SF were treated with TNF-α or a Wnt signaling inducer, and CIA joints were injected with a TNF-α antagonist. The expression of Snail in SF and joints was modulated by lentiviral vector-mediated transfer of cDNA or short hairpin RNA.
Results: There were higher expression levels of Snail and Cad-11 with a positive correlation in synovial tissues from RA patients and CIA rats. Stimulation with TNF-α or activation of Wnt signaling up-regulated the expression levels of Snail, Cad-11 and α-SMA in SF, and TNF-α antagonist therapy down-regulated their expression levels in CIA joints. While Snail-overexpressed SF transfectants had increased expression levels of Cad-11 and α-SMA and enhanced TNF-α-mediated invasive capacity and IL-6 production, Snail-knockdowned CIASF transfectants had decreased expression levels and the opposite effect on these functions. In addition, Snail-overexpressed normal rat joints had hyperplastic synovium with increased expression levels of Cad-11 and α-SMA. In CIA joints, silencing the expression of Snail ameliorated arthritis with reduced Cad-11 expression and extracellular matrix (ECM) deposition, whereas overexpressing Snail exacerbated arthritis with increased Cad-11 expression and ECM deposition.
Conclusion: This study demonstrates for the first time that transcription factor Snail regulates TNF-α-mediated activation of rheumatoid SF, and these findings might contribute to the pharmacological development of therapeutics targeting SF in RA patients.
C. R. Wang,
S. Y. Chen,
A. L. Shiau,
I. M. Jou,
M. F. Liu,
C. L. Wu,
« Back to 2014 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/regulation-of-tnf-%ce%b1-mediated-activation-of-rheumatoid-synovial-fibroblasts-by-transcription-factor-snail/