Over-expression of extracellular superoxide dismutase in mouse synovial tissue attenuates the inflammatory arthritis

Dong Hoon Yu,Jun Koo Yi,Hyung Soo Yuh,Sung Hyun Kim,Jeong Woong Lee,Ki Beom Bae,Na Ri Kim,Zae Young Ryoo,Seo Jin Park,Hei Jung Kim,Myoung Ok Kim,Do Hyung Kim,Si Jun Park,Young Rae Ji

doi:10.3858/emm.2012.44.9.060

Abstract

Oxidative stress such as reactive oxygen species (ROS) within the inflamed joint have been indicated as being involved as inflammatory mediators in the induction of arthritis. Correlations between extracellular-superoxide dismutase (EC-SOD) and inflammatory arthritis have been shown in several animal models of RA. However, there is a question whether the over-expression of EC-SOD on arthritic joint also could suppress the progression of disease or not. In the present study, the effect on the synovial tissue of experimental arthritis was investigated using EC-SOD over-expressing transgenic mice. The over-expression of EC-SOD in joint tissue was confirmed by RT-PCR and immunohistochemistry. The degree of the inflammation in EC-SOD transgenic mice was suppressed in the collagen-induced arthritis model. In a cytokine assay, the production of pro-inflammatory cytokines such as, IL-1β, TNFα, and matrix metalloproteinases (MMPs) was decreased in fibroblast-like synoviocyte (FLS) but not in peripheral blood. Histological examination also showed repressed cartilage destruction and bone in EC-SOD transgenic mice. In conclusion, these data suggest that the over-expression of EC-SOD in FLS contributes to the activation of FLS and protection from joint destruction by depressing the production of the pro-inflammatory cytokines and MMPs. These results provide EC-SOD transgenic mice with a useful animal model for inflammatory arthritis research.

Highlights

Rheumatoid arthritis (RA) is an autoimmune disease involving hyper-proliferation of the synovial membrane and accumulation of activated T cells and macrophages, leading to progressive joint destruction
The initiating event of RA is followed by the induction of an immune response that results in inflammation in the synovial membrane and the lining of the joint, that is usually composed of macrophage and fibroblast-like cells known as synoviocytes (Sweeney and Firestein, 2004)
The importance of maintaining a balance between oxidants and antioxidants in inflammatory diseases has been established by the amelioration of collagen-induced arthritis (CIA) by administration of extracellular-superoxide dismutase (EC-superoxide dismutase (SOD)) through gene transfer or by treatment with an SOD mimetic (Salvemini et al, 2001)

Summary

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease involving hyper-proliferation of the synovial membrane and accumulation of activated T cells and macrophages, leading to progressive joint destruction. The initiating event of RA is followed by the induction of an immune response that results in inflammation in the synovial membrane and the lining of the joint, that is usually composed of macrophage and fibroblast-like cells known as synoviocytes (Sweeney and Firestein, 2004) These cells can produce pro-inflammatory cytokines including tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6) and interleukin-8 (IL-8), which can enhance synovial inflam-. Vol 44(9), 529-535, 2012 mation (Feldmann, 1994) Oxidative stress such as reactive oxygen species (ROS) within the inflamed joint have been indicated as being involved as inflammatory mediators in the induction of arthritis (Goldring, 2004). ROS are responsible for collagen hydrolysis and activation of metalloproteinase, leading to the degradation of the extracellular matrix

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Conclusion