The pathology of rheumatoid arthritis (RA) includes synoviocytes proliferation, expression of inflammatory mediators, and persistent recruitment of immune cell; these might result from dysregulation of epigenetic control by histone acetylase (HDAC). The aim of this study is to examine the anti-arthritic effect of YH508, a histone deacetylse (HDAC) inhibitor, by in vitro and in vivo models. The IC50 values of YH508 against enzymatic activity of HDAC1, 2, 3, 6, and 8 significantly lower than an approved HDAC inhibitor SAHA (Vorinostat), indicates that YH508 is more potent than SAHA. Treatment with YH508 showed dose-dependent inhibition of cytokines (IL-6, nitric oxide, PGE2) secretion in RAW264.7 macrophages and RA synovial fibroblasts. In addition, YH508 dramatically suppressed M-CSF/RANKL induced osteoclastogenesis from macrophages at low concentration. Furthermore, these inhibitory effects were reversed by overexpression class I/II HDAC. In vivo anti-arthritic effects of YH508 were evaluated in a M. butyricum-induced arthritis model in rats. Oral administration of YH508 significantly inhibited paw swelling, bone destruction and reduced serum cytokine levels. Our results demonstrate that HDAC inhibitor YH508 inhibits the development of arthritis, suggest that it provides a new therapeutic approach for the treatment of inflammatory arthritis.
- Copyright © 2013 by The American Association of Immunologists, Inc.