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Research article
Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis
Yeong-Wook Song
Seoul National University
Corresponding Author
ORCiD: https://orcid.org/0000-0002-5384-3437
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Arthritis Research & Therapy.
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 (Treg) were induced from RA patients and co-cultured with healthy effector T cells (Teff) and cell proliferation was analyzed by flow cytometry. Finally, the effects of the inhibitor on the severity of arthritis was assessed in a murine model of adjuvant-induced arthritis (AIA).
Results
Overexpression of HDAC6 induced in 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. Also, 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 induces regulatory immune responses in 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.
Keywords
Rheumatoid arthritis, HDAC6, inflammation, inhibitor, drug
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CURRENT STATUS: Published
Version 2
Posted 23 Jun, 2020
Published
On 25 Jul, 2020
No community comments so far
Editorial decision: Accept
On 30 Jun, 2020
Review #2 received
Received 27 Jun, 2020
Review #1 received
Received 27 Jun, 2020
Reviewer #1 agreed
On 23 Jun, 2020
Editor assigned
On 23 Jun, 2020
Reviewer #2 agreed
On 23 Jun, 2020
Reviewers invited
Invitations sent on 23 Jun, 2020
Submission checks complete
On 22 Jun, 2020
Editor invited
On 22 Jun, 2020
No comments provided
Review #2 received
Received 30 May, 2020
Editorial decision: Major revision
On 30 May, 2020
Reviewer #2 agreed
On 15 May, 2020
Review #1 received
Received 12 May, 2020
Reviewer #1 agreed
On 10 May, 2020
Reviewers invited
Invitations sent on 07 May, 2020
Editor assigned
On 07 May, 2020
First submitted
On 06 May, 2020
Submission checks complete
On 06 May, 2020
Editor invited
On 06 May, 2020
Metrics
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Subject Areas
Rheumatology
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This preprint is under consideration at Arthritis Research & Therapy. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis
Yeong-Wook Song
Seoul National University
Corresponding Author
ORCiD: https://orcid.org/0000-0002-5384-3437
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Version 2
Posted 23 Jun, 2020
Published
On 25 Jul, 2020
No community comments so far
Editorial decision: Accept
On 30 Jun, 2020
Review #2 received
Received 27 Jun, 2020
Review #1 received
Received 27 Jun, 2020
Reviewer #1 agreed
On 23 Jun, 2020
Editor assigned
On 23 Jun, 2020
Reviewer #2 agreed
On 23 Jun, 2020
Reviewers invited
Invitations sent on 23 Jun, 2020
Submission checks complete
On 22 Jun, 2020
Editor invited
On 22 Jun, 2020
No comments provided
Review #2 received
Received 30 May, 2020
Editorial decision: Major revision
On 30 May, 2020
Reviewer #2 agreed
On 15 May, 2020
Review #1 received
Received 12 May, 2020
Reviewer #1 agreed
On 10 May, 2020
Reviewers invited
Invitations sent on 07 May, 2020
Editor assigned
On 07 May, 2020
First submitted
On 06 May, 2020
Submission checks complete
On 06 May, 2020
Editor invited
On 06 May, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Rheumatology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Arthritis Research & Therapy.
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 (Treg) were induced from RA patients and co-cultured with healthy effector T cells (Teff) and cell proliferation was analyzed by flow cytometry. Finally, the effects of the inhibitor on the severity of arthritis was assessed in a murine model of adjuvant-induced arthritis (AIA).
Results
Overexpression of HDAC6 induced in 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. Also, 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 induces regulatory immune responses in 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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5