Abstract
The aim of this paper was to investigate the protective effects of bromodomain containing 4 (BRD4) inhibition on the temporomandibular joint osteoarthritis (TMJ OA) induced by compressive mechanical stress and to explore the underlying mechanism. In vivo, a rat model of TMJ compressive loading device was used and BRD4 inhibitor was injected into the TMJ region. HE staining and micro-CT analysis were used for histological and radiographic assessment. Immunohistochemistry and qPCR were performed to detect inflammatory cytokines expressions. High-throughput ChIP-sequencing screening was performed to compare the BRD4 and H3K27ac binding patterns between condylar cartilage from control and mechanical force groups. In vitro, the mandibular condylar chondrocytes were treated with IL-1β. Small Interference RNA (siRNA) infection was used to silencing BRD4 or TREM1. qPCR was performed to detect inflammatory cytokines expressions. Our study showed that BRD4 inhibition can alleviate the thinning of condylar cartilage and subchondral bone resorption, as well as decrease the inflammatory factors expression both in vivo and in vitro. ChIP-seq analysis showed that BRD4 was more enriched in the promoter region of genes related to the stress and inflammatory pathways under mechanical stress in vivo. Trem1, a pro-inflammatory gene, was screened out from the overlapped BRD4 and H3K27ac increased binding sites, and Trem1 mRNA was found to be regulated by BRD4 inhibition both in vivo and in vitro. TREM1 inhibition reduced the expression of inflammatory factors induced by IL-1β in vitro. In summary, we concluded that BRD4 inhibition can protect TMJ OA-like pathological changes induced by mechanical stress and attenuate TREM1-mediated inflammatory response.
Highlights
Temporomandibular joint osteoarthritis (TMJ OA) is a traditionally defined degenerative joint disorder
We demonstrated that bromodomain containing 4 (BRD4) inhibition can reduce the TREM1-mediated inflammatory response after overloading mechanical stress or IL-1β treatment
Consistent with the thickness of the cartilage, the number of chondrocytes decreased in mechanical force (MF) group and increased in MF + JQ1 groups compared to MF group (Fig. 1c). These results suggested that BRD4 inhibitor JQ1 can effectively reduce the condylar cartilage thinning and chondrocytes loss caused by excessive mechanical stress
Summary
Temporomandibular joint osteoarthritis (TMJ OA) is a traditionally defined degenerative joint disorder. Huang et al Clin Epigenet (2021) 13:10 family which binds the acetylated histones and regulates transcription as an epigenetic reader [16]. BRD4 is considered as a potential therapeutic target in many inflammatory diseases [17,18,19,20,21,22]. It was reported that BRD4 has dual effects on the HMGB1 and NF-κB signaling pathways [18] and BRD4 can modulate macrophage inflammatory responses [17]. Several BRD4 inhibitors such as JQ1 were developed and proved to inhibit inflammation through blocking the interaction between BRD4 and acetylated histones [17,18,19, 25, 26]. Thereby, whether BRD4-mediated inflammatory response plays a key role in TMJ OA sparked our interest
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