Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21 WAF1/Cip1 expression

Keiichiro Nishida, Takamitsu Komiyama, Shinichi Miyazawa, Zheng Nan Shen, Takayuki Furumatsu, Hideyuki Doi, Aki Yoshida, Jiro Yamana, Masahiro Yamamura, Yoshihumi Ninomiya, Hajime Inoue, Hiroshi Asahara

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Abstract

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 p16 INK4a 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 liyperacetylation in the synovial cells and decreased the levels of tumor necrosis factor α and interieukin-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.

Original languageEnglish
Pages (from-to)3365-3376
Number of pages12
JournalArthritis and Rheumatism
Volume50
Issue number10
DOIs
Publication statusPublished - Oct 2004

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Histone Deacetylase Inhibitors
Autoantibodies
Arthritis
Fibroblasts
Rheumatoid Arthritis
Acetylation
Genetic Promoter Regions
Replacement Arthroplasties
romidepsin
Depsipeptides
Osteitis
Inbred DBA Mouse
Chromatin Immunoprecipitation
Cell Cycle Checkpoints
Transmission Electron Microscopy
Intravenous Injections
Intravenous Administration
Histones
Cartilage
Real-Time Polymerase Chain Reaction

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

Cite this

Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21 WAF1/Cip1 expression. / Nishida, Keiichiro; Komiyama, Takamitsu; Miyazawa, Shinichi; Shen, Zheng Nan; Furumatsu, Takayuki; Doi, Hideyuki; Yoshida, Aki; Yamana, Jiro; Yamamura, Masahiro; Ninomiya, Yoshihumi; Inoue, Hajime; Asahara, Hiroshi.

In: Arthritis and Rheumatism, Vol. 50, No. 10, 10.2004, p. 3365-3376.

Research output: Contribution to journalArticle

Nishida, Keiichiro ; Komiyama, Takamitsu ; Miyazawa, Shinichi ; Shen, Zheng Nan ; Furumatsu, Takayuki ; Doi, Hideyuki ; Yoshida, Aki ; Yamana, Jiro ; Yamamura, Masahiro ; Ninomiya, Yoshihumi ; Inoue, Hajime ; Asahara, Hiroshi. / Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21 WAF1/Cip1 expression. In: Arthritis and Rheumatism. 2004 ; Vol. 50, No. 10. pp. 3365-3376.
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abstract = "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 p16 INK4a 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 liyperacetylation in the synovial cells and decreased the levels of tumor necrosis factor α and interieukin-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.",
author = "Keiichiro Nishida and Takamitsu Komiyama and Shinichi Miyazawa and Shen, {Zheng Nan} and Takayuki Furumatsu and Hideyuki Doi and Aki Yoshida and Jiro Yamana and Masahiro Yamamura and Yoshihumi Ninomiya and Hajime Inoue and Hiroshi Asahara",
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T1 - Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21 WAF1/Cip1 expression

AU - Nishida, Keiichiro

AU - Komiyama, Takamitsu

AU - Miyazawa, Shinichi

AU - Shen, Zheng Nan

AU - Furumatsu, Takayuki

AU - Doi, Hideyuki

AU - Yoshida, Aki

AU - Yamana, Jiro

AU - Yamamura, Masahiro

AU - Ninomiya, Yoshihumi

AU - Inoue, Hajime

AU - Asahara, Hiroshi

PY - 2004/10

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N2 - 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 p16 INK4a 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 liyperacetylation in the synovial cells and decreased the levels of tumor necrosis factor α and interieukin-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.

AB - 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 p16 INK4a 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 liyperacetylation in the synovial cells and decreased the levels of tumor necrosis factor α and interieukin-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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