Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Importance of E3 Ubiquitin Ligase Synoviolin In Fibrogenesis.
Yagishita1, Naoko, Hasegawa1, Daisuke, Aratani2, Satoko, Yamano1, Yoshihisa, Nakajima2, Toshihiro
The symptoms of rheumatoid arthritis (RA) are based on the many processes; chronic inflammation, overgrowth of synovial cells, bone and joint destruction and fibrosis. To clarify the mechanism of outgrowth of synovial cells, we carried out immunoscreening using anti-rheumatoid synovial cell antibody, and cloned 'Synoviolin'. Synoviolin was highly expressed in the rheumatoid synovium, and confirmed that this molecule is one of the causative factors of arthropathy. Further analysis using gene targeting approaches showed that in addition to its role in RA, Synoviolin is essential for embryogenesis. Synoviolin deficient (syno-/-) mice exhibited severe anemia caused by enhancement of apoptosis in fetal liver, and the results suggested that the liver is sensitive organ for Synoviolin. Thus, this study aimed to explore the involvement of the Synoviolin in fibrosis process of RA using mice model of liver fibrosis.
The expression and localization of synoviolin in the liver were analyzed in CCl4-induced hepatic injury models and human cirrhosis tissues. The degree of liver fibrosis and the number of activated hepatic stellate cells (HSCs) was compared between wild type (WT) and synoviolin heterozygote (syno+/-) mice in the chronic hepatic injury model. We also analyzed the effect of synoviolin on collagen synthesis in the cell line from HSCs using siRNA-synoviolin and a mutant synoviolin in which E3 ligase activity was abolished. Furthermore, we compared collagen synthesis between WT and syno-/- mice embryonic fibroblasts (MEFs) using quantitative RT-PCR, western blotting, and collagen assay; then, we immunohistochemically analyzed the localization of collagen in syno-/- MEFs.
In CCl4-induced hepatic injury model, syno+/- mice are resistant to onset of liver fibrosis. The number of activated HSCs was decreased in syno+/- mice, and some of these cells showed apoptosis. Furthermore, collagen expression in HSCs was upregulated by synoviolin overexpression, while synoviolin knockdown led to reduced collagen expression. Moreover, in syno-/- MEFs, the amounts of intracellular and secreted mature collagen were significantly decreased, and procollagen was abnormally accumulated in the endoplasmic reticulum.
In conclusion, Synoviolin is involved in not only overgrowth process of synovial cells but also fibrosis process.
To cite this abstract, please use the following information:
Yagishita, Naoko, Hasegawa, Daisuke, Aratani, Satoko, Yamano, Yoshihisa, Nakajima, Toshihiro; Importance of E3 Ubiquitin Ligase Synoviolin In Fibrogenesis. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2080