Histone deacetylases (HDACs) are intracellular enzymes that regulate gene expression. They are divided into four classes according to structures, functions, cellular locations and expression patterns. HDAC inhibitors have traditionally been used as anti-cancer therapies due to their cytotoxic effects. Emerging evidence shows that such drugs might also be developed into anti-inflammatory agents if their side effects can be minimised to allow their long-term use to treat chronic diseases. Inhibitors selective for sub-classes of HDACs could be less cytotoxic and valuable probes for interrogating individual HDACs in inflammatory pathways.
In this study, we demonstrate that a novel and selective inhibitor of class IIa HDACs, both in vitro and in vivo, has anti-inflammatory activity in a rat model of arthritis. In human monocyte-derived macrophages, the inhibitor has minimal cytotoxicity. In a preclinical model of chronic joint inflammation, collagen is used to induce arthritis in Dark Agouti rats. Given prophylactically, the inhibitor of class IIa HDACs attenuates clinical signs of arthritic disease, substantially reducing paw swelling and bone destruction in arthritic rats according to micro-CT. It decreases collagen loss from joint surfaces and histological damage to the rat ankle. It lessens infiltration of immune cells into synovial joint spaces, most notably macrophages. In addition, expression levels of a number of pro-inflammatory cytokines, chemokines and tissue-degrading proteases are diminished. In conclusion, this study provides preliminary evidence for selective inhibitors of class IIa HDACs as efficacious experimental drug candidates for treating chronic inflammatory conditions. They might be especially useful for diseases in which macrophage infiltration plays a dominant role.