Punicalagin with anti-inflammatory activities affects Brd-4 mediated chromatin remodeling for attenuating inflammatory osteolysis

Inflammatory osteolysis is primarily characterized by an extensive macrophage-mediated inflammatory response coupled with osteoclast (OC) formation, triggered by bacterial byproducts and/or environmental stressors. And Osteoarthritis (OA) is one of the most common degenerative diseases in clinical medicine. Currently, anti-inflammatory drugs and intra-articular drug injection are mainly used, but the treatments only relieve symptoms. Punicalagin (PUN), a hydrolyzable tannin derived from pomegranate extract, the suppression of pro-inflammatory cytokine production in macrophages. The therapeutic potential of PUN in alleviating inflammatory osteolysis remains inadequately elucidated. PUN demonstrated favourable biocompatibility and therapeutic potential in vitro, including potent anti-osteoclastic activity, ROS scavenging capacity, and epigenetic regulatory functions. PUN was found to inhibit bromodomain-containing protein 4 (Brd4)-mediated chromatin space remodeling, consequently upregulating the production of endogenous anti-inflammatory factors and antioxidant factors. This study reveals a new therapeutic mechanism that PUN exerts anti-inflammatory effects and regulates epigenetic regulation by influencing Brd4-mediated chromatin remodeling. These findings showed the therapeutic potential of PUN for inflammatory diseases, especially inflammatory osteolysis. Notably, our work identifies a new strategy that synergistically combines osteoclast inhibition with epigenetic regulation, providing a promising direction for the therapies for bone-related inflammatory diseases.