Inhibition of Brd4 alleviates osteoarthritis pain via suppression of neuroinflammation and activation of Nrf2‐mediated antioxidant signalling

作者：Jia Sun, Xinghe Wang, Fan‐He Song, Danyang Li, Shao‐Jie Gao, Longqing Zhang, Jiayi Wu, Dai-Qiang Liu, Liwei Wang, Ya‐Qun Zhou, Wei Mei · 发表于：British Journal of Pharmacology · 年份：2023 · DOI：10.1111/bph.16195 · 被引用次数：17 · 研究领域：Protein Degradation and Inhibitors、Osteoarthritis Treatment and Mechanisms、Click Chemistry and Applications

BACKGROUND AND PURPOSE: Osteoarthritis (OA) pain remains a major clinical problem. It is urgent to identify novel therapeutic approaches for OA pain states. Bromodomain and extra-terminal (BET) protein inhibitors have robust anti-inflammatory effects in several pain models. However, the underlying mechanisms of these inhibitors in OA pain have not been determined. We, therefore, investigated the effects and the underlying mechanism(s) of BET inhibition on pain-related behaviours in a rat model of OA. EXPERIMENTAL APPROACH: The OA model was established by intra-articular injection of monosodium iodoacetate (MIA) in rat knees. Pain behaviours were assessed in rats by hindlimb weight-bearing asymmetry, mechanical allodynia and thermal hyperalgesia. Possible mechanisms underlying BET inhibition were explored in the MIA-induced OA pain model in the spinal cord and dorsal root ganglia (DRG). KEY RESULTS: Inhibiting bromodomain-containing protein 4 (Brd4) with either JQ1 or MS417, or using AAV2/9-shRNA-Brd4-EGFP-mediated knockdown of Brd4 genes, significantly attenuated MIA-induced pain behaviours. Brd4 inhibition suppressed NF-κB and NF-κB-mediated inflammatory cytokines in both the spinal cord and DRG in rats with MIA-induced OA pain. Brd4 inhibition also attenuated the oxidative stress and promoted nuclear factor erythroid-2-related factor 2 (Nrf2)-dependent antioxidant genes in both the spinal cord and DRG in our odel of MIA-induced OA pain. CONCLUSIONS AND IMPLICATIONS: In conc...