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Osteoarthritis (OA) has traditionally been defined as a non-inflammatory disease. Recently, many studies have demonstrated that OA also has an inflammatory component. BRD4, a member of the Bromodomain and Extra-Terminal Domain family, has emerged as an important regulator of some chronic inflammatory diseases. JQ1, an antagonist of BRD4, modulates transcription of several genes. Our study demonstrated that BRD4 is up-regulated in articular cartilage of OA. BRD4 inhibition attenuated the inflammation and catabolism of chondrocytes and suppressed NF-κB signalling pathway activation. In addition, BRD4 inhibition abolished the transcriptional activity of High Mobility Group Protein B1 (HMGB1). We identified HMGB1 as a direct target of BRD4. Genetic and pharmacological inhibition of BRD4 suppressed IL-1β-induced expression and translocation of HMGB1. Chromatin immunoprecipitation (ChIP) showed the enrichment of BRD4 around the HMGB1 upstream non-promoter region, which diminished with JQ1 treatment. Finally, haematoxylin & eosin and Safranin o/Fast Green staining demonstrated that JQ1 attenuates cartilage destruction in mice with anterior cruciate ligament transection without significant toxic effects. These studies highlighted the importance of BRD4 in the chronic inflammatory reactions of OA, which, as far as we know, was the first report of this finding, and suggested that BRD4 might be a novel potential therapeutic target for the treatment of OA. [ABSTRACT FROM AUTHOR]

[Display omitted] • CoP-challenged macrophages can accelerate osteoclastogenesis. • CoPs result in macrophages pyroptosis and release of inflammatory cytokines. • CoPs stimulation promotes ROS accumulation and subsequently activates NLRP3. • High-concentration CoPs suppress mitophagy, further enhancing macrophages pyroptosis. • By promoting mitophagy and inhibiting NLRP3, CoP-induced osteolysis can be delayed. Wear particles derived from implant surfaces are the important factors causing periprosthetic osteolysis (PPO), which is the main reason for total joint revision. To date, the specific pathogenesis of PPO remains largely unknown, and developing new therapeutic strategies is urgently necessary. Our study indicated the most clinically common cobalt- chromium-molybdenum (CoCrMo) wear particles (CoPs) activated macrophages and further accelerated osteoclastogenesis. Subsequently, we put emphasis on the pathologic change in macrophages after CoPs stimulation. Meaningfully, high-concentration CoPs induced reactive oxygen species (ROS) accumulation in macrophages and activated NOD-like receptor pyrin domain-containing 3 (NLRP3)-dependent pyroptosis, promoting the release of cytokines such as IL-18, IL-1β and HMGB1, and subsequent formation of extracellular inflammatory microenvironment, which is crucial for osteoclastogenesis. More interestingly, transmission electron microscopy and flow cytometry results revealed that there were accumulation of endamaged mitochondria in high-concentration CoP-challenged macrophages, which accelerated intracellular ROS accumulation and mediated NLRP3-dependent pyroptosis. Mechanismly, high-concentration CoPs induced macrophage mitophagy impairment and the loss of mitochondrial membrane potential via inhibiting PINK1/Parkin signalling pathway. Furthermore, by subcutaneous injection of salidroside and/or CY-09 in situ significantly delayed CoP-induced mice calvaria osteolysis. Collectively, this study demonstrates a novel mechanism underlying the pathogenesis of PPO and provides a potential therapy avenue. [ABSTRACT FROM AUTHOR]