Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.


A20 Gene Transfer Suppresses Inflammation and Bone Destruction through Inhibition of NF-Kappab Activation in Vitro and Vivo

Lee1,  Sang-IL, Kim2,  Hyun-Ok, Yoo3,  Wan Hee, Lee3,  Eun-Gyeong, Hong3,  Yun-Kyung, Kim4,  Sang-Hyon

College of Medicine, Gyeongsang National University, Jinju, South Korea
Gyongsang University, Jinju, South Korea
Chonbuk National University Medical School and Research Institute of Clinical Medicine. Jeonju, South Korea
Dongsan Medical Center, Keimyung University, Daegu, South Korea

Purpose:

The nuclear factor-kappaB (NF-kB) activation plays a pivotal role to develop inflammation and bone destruction in rheumatoid arthritis (RA), and A20 downregulates NF-kB activation through the cooperative activity of its two de-ubiquitination and ubiquitin ligase domains. However, there has been no study addressing whether A20 show the therapeutic efficacy in RA. Thus, the current study was performed to determine whether A20 can block the action of fibroblast-like synoviocytes (FLS) and also suppress disease activity and joint destruction in mouse model of collagen-induced arthritis (CIA).

Method:

The recombinant adenovirus carrying the gene that encodes A20 (Ad-A20) or beta-galactosidase (Ad-Bgal) were used. The inhibition of NF-kB activation and inflammatory chemokines/MMPs expression were assessed by EMSA and ELISA, respectively, after infection of Ad-A20 into FLS. The therapeutic effect was determined by clinical, histologic and immunostaining analyses after periarticular injection of Ad-A20 into the ankle joints of CIA mice. The inhibition of NF-kB activation was determined by EMSA and the levels of various cytokines in the joints and serum were measured by ELISA.

Results:

Infection of FLS with Ad-A20 inhibited TNFa-induced nuclear translocation and DNA binding of NF-kB. Ad-A20 suppressed production of chemokines, such as ENA-78 and RANTES, and activation of MMP-1 and MMP-3 in FLS. Periarticular injection of Ad-A20 significantly reduced the intensity of clinical manifestations and effectively prevented joint destruction in CIA. These inhibitory effects were paralleled by diminished DNA binding of NF-kB. Furthermore, A20 treatment suppressed levels of RANKL, TNFa, and IL-6.

Conclusion:

This study demonstrates that Ad-A20, most likely acts through inhibition of NF-kB activation, show therapeutic effects on inflammation and bone erosion in vitro and vivo. These results suggest that A20 can be used as a promising candidate in the field of treatment for RA.

To cite this abstract, please use the following information:
Lee, Sang-IL, Kim, Hyun-Ok, Yoo, Wan Hee, Lee, Eun-Gyeong, Hong, Yun-Kyung, Kim, Sang-Hyon; A20 Gene Transfer Suppresses Inflammation and Bone Destruction through Inhibition of NF-Kappab Activation in Vitro and Vivo [abstract]. Arthritis Rheum 2009;60 Suppl 10 :17
DOI: 10.1002/art.25100

Abstract Supplement

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2009 ACR/ARHP