Regulation of inflammation by histone deacetylases in rheumatoid arthritis: beyond epigenetics

The studies presented in this thesis demonstrate essential roles for histone deacetylase (HDAC) activity in regulating inflammatory responses of myeloid and stromal cells in rheumatoid arthritis (RA), and suggest that therapeutic targeting of HDACs with small molecule inhibitors might be useful in suppressing inflammation and joint destruction in RA patients. Our findings also identify two novel non-epigenetic mechanisms, namely reduction of target mRNA stability and modulation of FoxO1 expression and activity, which are at least partly responsible for anti-inflammatory effects of HDAC inhibitors. In light of a recent clinical trial demonstrating initial clinical efficacy of ITF2357 in patients with systemic onset juvenile idiopathic arthritis, future studies should be aimed at characterizing the specific roles of HDAC family members in cellular inflammatory activation, and verifying the suitability of either inhibiting total HDAC activity or targeting specific HDACs in therapeutic strategies in RA and other inflammatory disorders.