Role of DNA dioxygenase Ten-Eleven translocation 3 (TET3) in rheumatoid arthritis progression
Akio Kawabe, Kaoru Yamagata, Shigeaki Kato, Kazuhisa Nakano, Kei Sakata, Yu-ichi Tsukada, Koichiro Ohmura, Shingo Nakayamada, Yoshiya Tanaka
Abstract
BACKGROUND: Rheumatoid arthritis (RA) patients present with abnormal methylation patterns in their fibroblast-like synoviocytes (FLS). Given that DNA demethylation is critical for producing DNA methylation patterns, we hypothesized that DNA demethylation may facilitate RA progression. Therefore, we designed this study to examine the role of DNA dioxygenase family, Ten-Eleven translocation (TET1/2/3), in the pathological process of RA. METHODS: ) C57BL/6 mice. RESULTS: We found that both TET3 and 5-hydroxymethylcytosine (5hmC) were upregulated in synovitis tissues from RA patients and confirmed this upregulation in the cultured FLS derived from synovitis tissues. Tumor necrosis factor α (TNFα) upregulated TET3 and 5hmC levels in cultured FLS, and the stimulated FLS exhibited high cell mobility with increased transcription of cellular migration-related factors such as C-X-C motif chemokine ligand 8 (CXCL8) and C-C motif chemokine ligand 2 (CCL2) in a TET3-dependent manner. In addition, TET3 haploinsufficiency lowered RA progression in a mouse model of serum-induced arthritis. CONCLUSIONS: Based on these findings, we can assume that TET3-mediated DNA demethylation acts as an epigenetic regulator of RA progression.