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

• Published in: Journal of clinical periodontology 2023-12, Vol.50 (12), p.1658-1669
• Main Authors: Sun, Mingxu, Clayton, Nicholas, Alam, Sheikh, Asmussen, Niels, Wong, Andrew, Kim, Jin Ha, Luong, Gary, Mokhtari, Sasan, Pellei, David, Carrico, Caroline K, Schwartz, Zvi, Boyan, Barbara D, Giannobile, William V, Sahingur, Sinem Esra, Lin, Zhao
• Format: Article
• Language: English
• Subjects: Alveolar bone; Alveolar Bone Loss - drug therapy; Alveolar Bone Loss - pathology; Alveolar Bone Loss - prevention & control; Animals; Bone loss; Cell differentiation; Computed tomography; Cytokines; Epithelial cells; Gene expression; Gum disease; Humans; Inflammation; Inflammation - drug therapy; Macrophages; Osteoclastogenesis; Osteoclasts; Periodontitis; Periodontitis - drug therapy; Periodontitis - pathology; Periodontitis - prevention & control; Rats; Reverse transcription; Transcriptomes; X-Ray Microtomography
• ISSN: 0303-6979; 1600-051X; 1600-051X
• DOI: 10.1111/jcpe.13887

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. 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. 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. 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.