BRD4 has dual effects on the HMGB1 and NF-κB signalling pathways and is a potential therapeutic target for osteoarthritis

Abstract

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.

BRD4 inhibition attenuates inflammatory response in microglia and facilitates recovery after spinal cord injury in rats

“…30 Due to the critical role of BRD4 in inflammatory response in other cell types, 12,29 we explored the underlying mechanism of BRD4 inhibition on microglial activation in vitro. 17 In line with these observations, we found that BRD4 knockdown and JQ1 both up-regulated the level of IκBα and inhibited phosphorylation of p65, thus blocking the activation of the NF-κB signalling pathway. 12 In addition, BRD4 knockdown inhibits the NF-κB signalling pathway by promoting the level of IκBα and preventing phosphorylation of p65 in IL-1β-treated chondrocytes.…”

“…12,13 Under pathological conditions, the phosphorylation of p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK) and extracellular signal regulated kinase (ERK) is markedly increased in microglia, which may lead to increased expression of pro-inflammatory phenotypes such as TNF-α, IL-1β, IL-6 and INOS. 17,18 In the present study, we found that BRD4 level was correlated with pro-inflammatory cytokines after SCI in rats. 15 BRD4 inhibition by JQ1 was demonstrated to attenuate LPS-induced expression of pro-inflammatory cytokines and suppressed inflammatory reactions in macrophages; 16 studies also showed that JQ1 negatively modulates inflammation in rheumatoid arthritis and osteoarthritis indicating that suppression of BRD4 might be a potential therapeutic method against inflammatory response in SCI.…”

“…12,17 To evaluate the pro-inflammatory microenvironment after SCI, we detected the levels of TNF-α, IL-β and IL-6 in injured spinal cord. 12,17 To evaluate the pro-inflammatory microenvironment after SCI, we detected the levels of TNF-α, IL-β and IL-6 in injured spinal cord.…”

“…12,17 To evaluate the pro-inflammatory microenvironment after SCI, we detected the levels of TNF-α, IL-β and IL-6 in injured spinal cord. 17,20 To test BRD4 activation in microglia after SCI, we collected the T7-T10 level around the lesion part of the spinal cord to detect the gross level of BRD4 in the spinal cord. It is reported that BRD4 is implicated with pro-inflammatory phenotypes in various cell types and microglia play a critical role in inflammatory response in the central nervous system.…”

Bromodomain‐containing protein 4 inhibition alleviates matrix degradation by enhancing autophagy and suppressing NLRP3 inflammasome activity in NP cells

“…Substantial evidence has revealed that pro‐inflammatory molecules contribute to aggrecan and collagen II degradation and pro‐inflammatory cytokine expression (Johnson et al, 2015; Kang et al, 2015; Molinos et al, 2015; Wang et al, 2017). In addition, BRD4 is upregulated in articular cartilage, and BRD4 inhibition prevents inflammation in osteoarthritis and synovial inflammation (Jiang et al, 2017; Xiao et al, 2016; Xu & Vakoc, 2014). Similarly, our data showed that TNF‐α induced the expression of BRD4 in NP cells, while BRD4 inhibition by JQ1 alleviated matrix degradation in NP cells.…”