Silencing Intraarticular Snail Expression Ameliorates Rat Collagen-Induced Arthritis Through Induction of Mesenchymal-Epithelial Transition in Synovial Fibroblasts

Chrong-Reen Wang¹, Shih-Yao Chen², Ai-Li Shiau³, Yuan-Tsung Li⁴, Ming-Fei Liu⁵ and Chao-Liang Wu², ¹Section of Rheumatology and Immunology, Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ²Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan, ³Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan, ⁴Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ⁵Internal Medicine, National Cheng Kung University Medical College, Tainan, Taiwan

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Animal models, cadherin-11, rheumatoid arthritis, synovial fluid, treatment and synovial cells

Session Information

Title: Rheumatoid Arthritis: Animal Models

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Morphological characteristics of rheumatoid arthritis (RA) synovial fibroblasts (SF) are similar to transformed cells. We hypothesized that epithelial-mesenchymal transition (EMT) of SF regulated by snail contributes to the progression of RA. The pathogenic role of EMT was studied, and the therapeutic effect on arthritis was evaluated by silencing intraarticular snail expression.

Methods:

Expression of snail, mesenchymal markers including cadherin-11, epitheral markers and/or phospho-AKT was detected by RT-PCR, immunoblot and/or immunohistochemical analyses on RA synovium, and synovial tissues and SF from normal or collagen-induced arthritis (CIA) rats. Modulation of in vitro expression in SF and in vivo effect on normal or CIA joints was performed by lentivirus-mediated transfer of cDNA or shRNA specific to snail. In vivo responses were evaluated by clinical and histopathological assessments, and immunohistochemical staining on joints. In vitro cell viability and invasion were determined by colorimeric method and modified Boyden chamber, respectively. IL-6 concentrations in culture supernatants were quantified by enzyme-linked immunosorbent assay.

Results:

Snail was expressed at high levels in synovial tissues of RA and CIA. Overexpression of snail in SF and joints of normal rats promoted EMT by down-regulation of epithelial markers, gain of mesenchymal markers and enhancement of invasive capacity. Moreover, silencing snail expression ameliorated CIA through the induction of mesenchymal-epithelial transition.

Conclusion:

These data demonstrate that regulation of snail in SF alters cell morphology and gene expression between epithelial and mesenchymal phenotypes. These findings implicate that EMT regulated by snail might be explored as a novel therapeutic strategy targeting SF in RA.

Disclosure:

C. R. Wang,
None;

S. Y. Chen,
None;

A. L. Shiau,
None;

Y. T. Li,
None;

M. F. Liu,
None;

C. L. Wu,
None.

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