Histone acetylation, BET proteins, and periodontal inflammation.

Periodontitis is one of the most common inflammatory diseases in humans. The susceptibility to periodontitis is largely determined by the host response, and the severity of inflammation predicts disease progression. Upon microbial insults, host cells undergo massive changes in their transcription program to trigger an appropriate response (inflammation). It is not surprising that successful keystone pathogens have developed specific mechanisms to manipulate the gene expression network in host cells. Emerging data has indicated that epigenetic regulation plays a significant role in inflammation. Acetylation of lysine residues on histones is a major epigenetic modification of chromatin, highly associated with the accessibility of chromatin and activation of transcription. Specific histone acetylation patterns are observed in inflammatory diseases including periodontitis. Bromo- and extraterminal domain (BET) proteins recognize acetylated histones and then recruit transcription factors and transcription elongation complexes to chromatin. BET proteins are regulated in inflammatory diseases and small molecules blocking the function of BET proteins are promising "epi-drugs" for treating inflammatory diseases.

Selective BET inhibitor RVX-208 ameliorates periodontal inflammation and bone loss.

AIM: To determine the effects of RVX-208, a selective bromodomain and extra-terminal domain (BET) inhibitor targeting bromodomain 2 (BD2), on periodontal inflammation and bone loss. MATERIALS AND METHODS: Macrophage-like cells (RAW264.7) and human gingival epithelial cells were challenged by Porphyromonas gingivalis (Pg) with or without RVX-208. Inflammatory gene expression and cytokine production were measured by reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RAW264.7 cells were induced to osteoclast differentiation. After RVX-208 treatment, osteoclast differentiation was evaluated by histology, tartrate-resistant-acid-phosphatase (TRAP) activity and the expression of osteoclast-specific genes. The effect of RVX-208 on osteoclast transcriptome was studied by RNA sequencing. Periodontitis was induced in rats by ligature and local RVX-208 treatment was administered every other day. Alveolar bone loss was measured by micro-computed tomography. RESULTS: RVX-208 inhibited inflammatory gene expression and cytokine production in Pg-infected cells. Osteoclast differentiation was inhibited by RVX-208, as evidenced by reduced osteoclast number, TRAP activity and osteoclast-specific gene expression. RVX-208 displayed a more selective and less profound suppressive impact on transcriptome compared with pan-BET inhibitor, JQ1. RVX-208 administration prevented the alveolar bone loss in vivo. CONCLUSIONS: RVX-208 regulated both upstream (inflammatory cytokine production) and downstream (osteoclast differentiation) events that lead to periodontal tissue destruction, suggesting that it may be a promising 'epi-drug' for the prevention of periodontitis.