Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21WAF1/Cip1 expression
Corresponding Author
Keiichiro Nishida
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Department of Human Morphology, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, JapanSearch for more papers by this authorTakamitsu Komiyama
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorShin-ichi Miyazawa
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorZheng-Nan Shen
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorTakayuki Furumatsu
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorHideyuki Doi
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorAki Yoshida
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorJiro Yamana
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorMasahiro Yamamura
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorYoshihumi Ninomiya
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorHajime Inoue
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorHiroshi Asahara
The Scripps Research Institute, La Jolla, California
Search for more papers by this authorCorresponding Author
Keiichiro Nishida
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Department of Human Morphology, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, JapanSearch for more papers by this authorTakamitsu Komiyama
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorShin-ichi Miyazawa
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorZheng-Nan Shen
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorTakayuki Furumatsu
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorHideyuki Doi
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorAki Yoshida
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorJiro Yamana
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorMasahiro Yamamura
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorYoshihumi Ninomiya
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorHajime Inoue
Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
Search for more papers by this authorHiroshi Asahara
The Scripps Research Institute, La Jolla, California
Search for more papers by this authorAbstract
Objective
To examine whether depsipeptide (FK228), a histone deacetylase (HDA) inhibitor, has inhibitory effects on the proliferation of synovial fibroblasts from rheumatoid arthritis (RA) patients, and to examine the effects of systemic administration of FK228 in an animal model of arthritis.
Methods
Autoantibody-mediated arthritis (AMA) was induced in 19 male DBA/1 mice (6–7 weeks old); 10 of them were treated by intravenous administration of FK228 (2.5 mg/kg), and 9 were used as controls. The effects of FK228 were examined by radiographic, histologic, and immunohistochemical analyses and arthritis scores. RA synovial fibroblasts (RASFs) were obtained at the time of joint replacement surgery. In vitro effects of FK228 on cell proliferation were assessed by MTT assay. Cell morphology was examined by light and transmission electron microscopy. The effects on the expression of the cell cycle regulators p16INK4a and p21WAF1/Cip1 were examined by real-time polymerase chain reaction and Western blot analysis. The acetylation status of the promoter regions of p16INK4a and p21WAF1/Cip1 were determined by chromatin immunoprecipitation assay.
Results
A single intravenous injection of FK228 (2.5 mg/ml) successfully inhibited joint swelling, synovial inflammation, and subsequent bone and cartilage destruction in mice with AMA. FK228 treatment induced histone hyperacetylation in the synovial cells and decreased the levels of tumor necrosis factor α and interleukin-1β in the synovial tissues of mice with AMA. FK228 inhibited the in vitro proliferation of RASFs in a dose-dependent manner. Treatment of cells with FK228 induced the expression of p16INK4a and up-regulated the expression of p21WAF1/Cip1. These effects of FK228 on p16INK4a and p21WAF1/Cip1 were related to the acetylation of the promoter region of the genes.
Conclusion
Our findings strongly suggest that systemic administration of HDA inhibitors may represent a novel therapeutic target in RA by means of cell cycle arrest in RASFs via induction of p16INK4a expression and increase in p21WAF1/Cip1 expression.
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