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M-134, a novel HDAC6-selective inhibitor, markedly improved arthritic severity in a rodent model of rheumatoid arthritis when combined with tofacitinib

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Abstract

Background

Although tofacitinib has shown highly significant efficacy for rheumatoid arthritis (RA), there are still a considerable number of patients that are non-responders owing to its limited effectiveness and various adverse effects. Thus, alternative options with better efficacy and lower toxicity are desired. Here, M-134, a recently developed HDAC6 inhibitor, was examined for its therapeutic potential when combined with tofacitinib in a rat model of RA.

Methods

The single or combined administration of M-134 and tofacitinib was examined in complete Freund’s adjuvant-induced arthritis (AIA) or collagen-induced arthritis (CIA) rodent models. To evaluate the therapeutic and adverse effects, the following factors were observed: macroscopic or microscopic scoring of all four paws; the expression of ICAM-1, VCAM-1, and IP-10 in the joints and that of various cytokines and chemokines in the plasma; the weight of the thymus and the liver; and changes in hematological enzymes.

Results

Combination treatment showed strong synergistic effects as measured by the clinical score and histological changes, without adverse effects such as weight loss in the thymus and increased liver enzymes (ALT and AST). Additionally, it also reduced ICAM-1, VCAM-1, and IP-10 expression in the joints, and M-134 increased the efficacy of tofacitinib by regulating various cytokines, such as interleukin (IL)-1β, IL-17, and TNF-α, in the serum of AIA rats. Differences in the cytokine expression for each drug were found in the CIA model.

Conclusions

M-134 and tofacitinib combination therapy is a potential option for the treatment of RA through the regulation of cytokines, chemokines, and adhesion molecules.

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Abbreviations

AIA:

Adjuvant-induced arthritis

CIA:

Collagen-induced arthritis

HDAC:

Histone deacetylase

IL:

Interleukin

JAK:

Janus kinase

RA:

Rheumatoid arthritis

TNF:

Tumor necrosis factor

TGF:

Transforming growth factor

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Funding

We would like to thank the scientists of the Department of Pharmacology, Chong Kun Dang Hyo-Jong Research Institute for their technical support and assistance. This study was supported by research grants from CKD Pharmaceuticals.

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Authors and Affiliations

  1. Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea

    Daekwon Bae

  2. Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea

    Jiyoung Lee & Woochan Son

  3. Department of Pharmacology, CKD Research Institute, CKD Pharmaceutical Co, Yongin, Republic of Korea

    Daekwon Bae, Youngil Choi, Nina Ha, Donghyeon Suh, Jiyeon Baek & Jinsol Park

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  1. Daekwon Bae
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Contributions

WCS and DKB were responsible for the study design. DKB, DHS, JTB, JSP, and JYL performed the animal test and histopathological experiments. DKB performed histological and molecular biological analyses. DKB, NH, YIC, and WCS interpreted the results, contributed to the discussion, and edited the manuscript. All the authors contributed to the interpretation of data and approved the final draft.

Corresponding author

Correspondence to Woochan Son.

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Conflict of interest

DKB, YIC, NH, DHS, and JYB are employees of CKD Research Institute. The other authors declare no conflict of interest.

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Bae, D., Choi, Y., Lee, J. et al. M-134, a novel HDAC6-selective inhibitor, markedly improved arthritic severity in a rodent model of rheumatoid arthritis when combined with tofacitinib. Pharmacol. Rep 73, 185–201 (2021). https://doi.org/10.1007/s43440-020-00188-x

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