Background/Purpose: Histone deacetylases (HDAC) play a key role in regulating gene expression by deacetylasing histones, and HDAC inhibitors induce various cellular effects, including apoptosis, cell cycle arrest and inhibition of angiogenesis. Tubastatin A is a potent and selective HDAC-6 inhibitor and its anti-rheumatic effect has not been determined. This study was undertaken to investigate the effect of Tubastatin A on synovial inflammation and joint destruction in collagen antibody-induced arthritis (CAIA) mouse model.

Methods: CAIA mice were given daily intraperitonial injections of various concentration of Tubastatin A (0, 10, 50, 100mg/kg, n=6 each). Clinical score, paw thickness, and body weight were measured for 14 days. On day 15, mice were sacrificed and the expression of TNF-α, IL-1, IL-6 from the serum was analyzed using ELISA. Hind foot was examined histologically and synovitis was scored by 2 independent pathologists. Micro CT of the joints was performed and joint destruction was quantified. Cell viability and the expression of inflammatory cytokines in human fibroblast-like synoviocytes (FLS) after incubation with various doses of Tubastatin A (0, 0.75, 1.5, 3μM) were measured using MTT assay and ELISA, respectively.

Results: In the Tubastatin A-treated group, clinical arthritis was attenuated and paw thickness was lower and this effect was statistically significant in the Tubastatin 100mg/kg group compared to control (p<0.01). All mice lost a small amount of weight but the difference was not statistically significant between groups. In the Tubastatin A 100mg/kg group, the histological severity of synovial inflammation as measured by synovial hypertrophy, density of resident cells, and inflammatory cell infiltrates was significantly lower compared with control (p<0.01, each). In addition, micro CT showed that joint destructions as measured by bone volume/tissue volume and bone surface area/bone volume were significantly less in the Tubastatin 100mg/kg group compared with control (p<0.05). Among pro-inflammatory cytokines, expression of IL-6 in the serum was significantly lower in the Tubastatin A 50mg/kg group compared with control (p<0.05). The expression of IL-6 from human FLS after incubation with Tubastatin A decreased in a dose-dependent manner without affecting the cell viability.

Conclusion: Our data demonstrated that Tubastatin A, a selective HDAC6 inhibitor, ameliorates synovial inflammation and protects against joint destruction in CAIA mice, and reduced expression of IL-6. Our data suggest that Tubastatin A warrant further investigation as a potential therapeutic agent in rheumatoid arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tubastatin-a-a-selective-histone-deacetylase-6-inhibitor-suppresses-synovial-inflammation-and-joint-destruction-in-a-collagen-antibody-induced-arthritis-mouse-model/