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Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis

OBJECTIVES: Histone deacetylase (HDAC) 6 promotes inflammation. We investigated the anti-arthritic effects of CKD-506, a novel HDAC6 inhibitor, in vitro and in a murine model of arthritis as a novel treatment option for rheumatoid arthritis (RA). METHODS: HDAC6 was overexpressed in mouse peritoneal...

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Autores principales: Park, Jin Kyun, Jang, Yu Jin, Oh, Bo Ram, Shin, Jieun, Bae, Daekwon, Ha, Nina, Choi, Young il, Youn, Gi Soo, Park, Jinseu, Lee, Eun Young, Lee, Eun Bong, Song, Yeong Wook
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382061/
https://www.ncbi.nlm.nih.gov/pubmed/32711562
http://dx.doi.org/10.1186/s13075-020-02258-0
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author Park, Jin Kyun
Jang, Yu Jin
Oh, Bo Ram
Shin, Jieun
Bae, Daekwon
Ha, Nina
Choi, Young il
Youn, Gi Soo
Park, Jinseu
Lee, Eun Young
Lee, Eun Bong
Song, Yeong Wook
author_facet Park, Jin Kyun
Jang, Yu Jin
Oh, Bo Ram
Shin, Jieun
Bae, Daekwon
Ha, Nina
Choi, Young il
Youn, Gi Soo
Park, Jinseu
Lee, Eun Young
Lee, Eun Bong
Song, Yeong Wook
author_sort Park, Jin Kyun
collection PubMed
description OBJECTIVES: Histone deacetylase (HDAC) 6 promotes inflammation. We investigated the anti-arthritic effects of CKD-506, a novel HDAC6 inhibitor, in vitro and in a murine model of arthritis as a novel treatment option for rheumatoid arthritis (RA). METHODS: HDAC6 was overexpressed in mouse peritoneal macrophages and RAW 264.7 cells, and the effects of a HDAC6 inhibitor CKD-506 on cytokine production and activity of NF-κB and AP-1 signaling were examined. Peripheral blood mononuclear cells (PBMCs) from RA patients and fibroblast-like synoviocytes (FLS) were activated in the presence of CKD-506. Next, regulatory T cells (Tregs) were induced from RA patients and co-cultured with healthy effector T cells (Teffs) and cell proliferation was analyzed by flow cytometry. Finally, the effects of the inhibitor on the severity of arthritis were assessed in a murine model of adjuvant-induced arthritis (AIA). RESULTS: Overexpression of HDAC6 induced macrophages to produce TNF-α and IL-6. The inhibitory effect of CKD-506 was mediated via blockade of NF-κB and AP-1 activation. HDAC6 inhibition reduced TNF-α and IL-6 production by activated RA PBMCs. CKD-506 inhibited production of MMP-1, MMP-3, IL-6, and IL-8 by activated FLS. In addition, CKD-506 inhibited proliferation of Teffs directly and indirectly by improving iTreg function. In AIA rats, oral CKD-506 improved clinical arthritis in a dose-dependent manner. A combination of sub-therapeutic CKD-506 and methotrexate exerted a synergistic effect. CONCLUSION: The novel HDAC6 inhibitor CKD-506 suppresses inflammatory responses by monocytes/macrophages, improves Treg function, and ameliorates arthritis severity in a murine model of RA. Thus, CKD-506 might be a novel and effective treatment option for RA.
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spelling pubmed-73820612020-07-27 Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis Park, Jin Kyun Jang, Yu Jin Oh, Bo Ram Shin, Jieun Bae, Daekwon Ha, Nina Choi, Young il Youn, Gi Soo Park, Jinseu Lee, Eun Young Lee, Eun Bong Song, Yeong Wook Arthritis Res Ther Research Article OBJECTIVES: Histone deacetylase (HDAC) 6 promotes inflammation. We investigated the anti-arthritic effects of CKD-506, a novel HDAC6 inhibitor, in vitro and in a murine model of arthritis as a novel treatment option for rheumatoid arthritis (RA). METHODS: HDAC6 was overexpressed in mouse peritoneal macrophages and RAW 264.7 cells, and the effects of a HDAC6 inhibitor CKD-506 on cytokine production and activity of NF-κB and AP-1 signaling were examined. Peripheral blood mononuclear cells (PBMCs) from RA patients and fibroblast-like synoviocytes (FLS) were activated in the presence of CKD-506. Next, regulatory T cells (Tregs) were induced from RA patients and co-cultured with healthy effector T cells (Teffs) and cell proliferation was analyzed by flow cytometry. Finally, the effects of the inhibitor on the severity of arthritis were assessed in a murine model of adjuvant-induced arthritis (AIA). RESULTS: Overexpression of HDAC6 induced macrophages to produce TNF-α and IL-6. The inhibitory effect of CKD-506 was mediated via blockade of NF-κB and AP-1 activation. HDAC6 inhibition reduced TNF-α and IL-6 production by activated RA PBMCs. CKD-506 inhibited production of MMP-1, MMP-3, IL-6, and IL-8 by activated FLS. In addition, CKD-506 inhibited proliferation of Teffs directly and indirectly by improving iTreg function. In AIA rats, oral CKD-506 improved clinical arthritis in a dose-dependent manner. A combination of sub-therapeutic CKD-506 and methotrexate exerted a synergistic effect. CONCLUSION: The novel HDAC6 inhibitor CKD-506 suppresses inflammatory responses by monocytes/macrophages, improves Treg function, and ameliorates arthritis severity in a murine model of RA. Thus, CKD-506 might be a novel and effective treatment option for RA. BioMed Central 2020-07-25 2020 /pmc/articles/PMC7382061/ /pubmed/32711562 http://dx.doi.org/10.1186/s13075-020-02258-0 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Park, Jin Kyun
Jang, Yu Jin
Oh, Bo Ram
Shin, Jieun
Bae, Daekwon
Ha, Nina
Choi, Young il
Youn, Gi Soo
Park, Jinseu
Lee, Eun Young
Lee, Eun Bong
Song, Yeong Wook
Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis
title Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis
title_full Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis
title_fullStr Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis
title_full_unstemmed Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis
title_short Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis
title_sort therapeutic potential of ckd-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382061/
https://www.ncbi.nlm.nih.gov/pubmed/32711562
http://dx.doi.org/10.1186/s13075-020-02258-0
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