Background/Purpose:  Rheumatoid Arthritis (RA) is a chronic inflammatory autoimmune disease whose etiology is unclear. Recently, upregulated HDAC (histone deacetylase) activity has been reported in peripheral blood mononuclear cell (PBMC) from RA patient. In addition, it was reported that HDAC6 inhibitor (HDAC6i) improves cancers and inflammatory diseases by suppressing cell migration and proliferation and reducing pro-inflammatory cytokines such as TNF-α. Here, we investigated the therapeutic effects of a new HDAC6 inhibitor, CKD-M808 (M808), specifically targeting catalytic domain 1 of HDAC6 in RA.

Methods:  We made adjuvant induced arthritis (AIA) model by injection of complete Freund’s adjuvant (CFA) subcutaneously into the tail base of Lewis rat on the 1^st day of experiment. Vehicle (n=9) and M808 (10, 30, 50 and 100 mg/kg, n=9, 9, 8 and 10, respectively) were administered orally every day. Clinical score was measured at 10^th, 14^th and 17^th days after induction. PBMC from RA patients were treated with HDAC6i (Tubastatin A and M808) for 24 hours under lipopolysaccharide (LPS) stimulation. After incubation, cell viability and the levels of cytokines including TNF-α, IL-1ß, IL-6 and IL-10 in culture supernatant were measured using CCK-8 and multiplex ELISA assay, respectively. Fibroblast-like synoviocyte (FLS) from RA patients were treated with HDAC6i for 24 hours under IL-1ß stimulation. The levels of IL-6, MMP-1 and MMP-3 were measured in culture supernatant. Cortactin and acetylated cortactin in HDAC6i-treated RA-FLS were measured by Western blotting.

Results:  Clinical score of AIA model were significantly decreased as the dose of M808 increased, indicating the therapeutic effect of M808. In RA-PBMC, M808 downregulated the level of TNF-α<span ‘arial’,’sans-serif’;”=”‘Arial’,’sans-serif’;”” lang=”EN-US”> and upregulated the level of IL-10 without any impact on cell viability. In RA-FLS, M808 decreased the production of MMP-1 and MMP-3. M808 increased acetylation of cortactin molecule in a dose-dependent manner.

Conclusion:  M808 suppressed clinical arthritis in the AIA model. M808 decreased the production of TNF-α and increased IL-10 in PBMC of RA patients. M808 also decreased MMP-1 and MMP-3 in FLS of RA patients. The novel HDAC6i, M808, may provide a new therapeutic option in RA patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/therapeutic-role-of-a-novel-histone-deacetylase-6-inhibitor-ckd-m808-in-rheumatoid-arthritis/