Regulation of TNF-α-Mediated Activation of Rheumatoid Synovial Fibroblasts By Transcription Factor Snail

Chrong-Reen Wang^1,2, Shih-Yao Chen³, Ai-Li Shiau⁴, I-Ming Jou^5,6, Ming-Fei Liu^1,2 and Chao-Liang Wu³, ¹Internal Medicine, National Cheng Kung University Medical College, Tainan, Taiwan, ²Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, ³Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan, ⁴Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan, ⁵Orthopedics, National Cheng Kung University Medical College, Tainan, Taiwan, ⁶Orthopedics, National Cheng Kung University Hospital, Tainan, Taiwan

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Animal models, Fibroblasts, rheumatoid arthritis, Rheumatoid arthritis (RA), synovium and transcription factor

Session Information

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.

Disclosure:

C. R. Wang,
None;

S. Y. Chen,
None;

A. L. Shiau,
None;

I. M. Jou,
None;

M. F. Liu,
None;

C. L. Wu,
None.

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