The HDAC2-selective inhibitor KTT-1 attenuates autoimmune arthritis by inhibiting osteoclast differentiation in mice

Histone deacetylases (HDACs) are crucial epigenetic regulators of gene expression through the reversible acetylation of lysine residues, and their inhibition is known to exert anti-arthritic effects. Given the critical role of osteoclasts in bone destruction in rheumatoid arthritis (RA) pathogenesis, targeting HDAC2—whose expression is upregulated during osteoclast differentiation—represents a promising therapeutic strategy. Although the development of highly specific HDAC2 inhibitors has recently attracted considerable attention, no such inhibitor has yet been successfully developed. In the current study, we found that the kinetic-selective HDAC2 inhibitor KTT-1 effectively suppressed arthritis symptoms in the collagen-induced arthritis (CIA) mouse model without causing severe side effects. Furthermore, KTT-1 inhibited osteoclast differentiation at an early stage by downregulating c-Fos expression, suggesting that the KTT-1-mediated anti-arthritis effect was achieved by inhibiting osteoclast differentiation. These findings highlight KTT-1 as a promising therapeutic candidate for the development of targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs).