Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis
Abstract 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 peri...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-07-01
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| Series: | Arthritis Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13075-020-02258-0 |
| _version_ | 1819207171770941440 |
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| author | Jin Kyun Park Yu Jin Jang Bo Ram Oh Jieun Shin Daekwon Bae Nina Ha Young il Choi Gi Soo Youn Jinseu Park Eun Young Lee Eun Bong Lee Yeong Wook Song |
| author_facet | Jin Kyun Park Yu Jin Jang Bo Ram Oh Jieun Shin Daekwon Bae Nina Ha Young il Choi Gi Soo Youn Jinseu Park Eun Young Lee Eun Bong Lee Yeong Wook Song |
| author_sort | Jin Kyun Park |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-23T05:19:15Z |
| format | Article |
| id | doaj.art-ec12f8ed6ac94d528286a8f11c4b8039 |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-12-23T05:19:15Z |
| publishDate | 2020-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-ec12f8ed6ac94d528286a8f11c4b80392022-12-21T17:58:44ZengBMCArthritis Research & Therapy1478-63622020-07-012211910.1186/s13075-020-02258-0Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritisJin Kyun Park0Yu Jin Jang1Bo Ram Oh2Jieun Shin3Daekwon Bae4Nina Ha5Young il Choi6Gi Soo Youn7Jinseu Park8Eun Young Lee9Eun Bong Lee10Yeong Wook Song11Division of Rheumatology, Department of Internal Medicine, Seoul National University College of MedicineDepartment of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National UniversityDepartment of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National UniversityDepartment of Pharmacology and Toxicology, CKD Research Institute, CKD Pharmaceutical CompanyDepartment of Pharmacology and Toxicology, CKD Research Institute, CKD Pharmaceutical CompanyDepartment of Pharmacology and Toxicology, CKD Research Institute, CKD Pharmaceutical CompanyDepartment of Pharmacology and Toxicology, CKD Research Institute, CKD Pharmaceutical CompanyDepartment of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym UniversityDepartment of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym UniversityDivision of Rheumatology, Department of Internal Medicine, Seoul National University College of MedicineDivision of Rheumatology, Department of Internal Medicine, Seoul National University College of MedicineDivision of Rheumatology, Department of Internal Medicine, Seoul National University College of MedicineAbstract 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.http://link.springer.com/article/10.1186/s13075-020-02258-0Rheumatoid arthritisHDAC6InflammationInhibitorDrug |
| spellingShingle | Jin Kyun Park Yu Jin Jang Bo Ram Oh Jieun Shin Daekwon Bae Nina Ha Young il Choi Gi Soo Youn Jinseu Park Eun Young Lee Eun Bong Lee Yeong Wook Song Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis Arthritis Research & Therapy Rheumatoid arthritis HDAC6 Inflammation Inhibitor Drug |
| 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 | Rheumatoid arthritis HDAC6 Inflammation Inhibitor Drug |
| url | http://link.springer.com/article/10.1186/s13075-020-02258-0 |
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