Department of Anesthesiology, Xuzhou Central Hospital, Xuzhou, China.
Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Br J Pharmacol. 2023 Dec;180(24):3194-3214. doi: 10.1111/bph.16195. Epub 2023 Aug 23.
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.
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).
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.
In conclusion, Brd4 inhibition alleviated MIA-induced OA pain in rats, via suppression of neuroinflammation and activation of Nrf2-mediated antioxidant signalling. Although our model does not perfectly represent how OA develops in humans, inhibition of Brd4 may provide novel insights into possible treatments for OA pain.
骨关节炎（OA）疼痛仍是一个主要的临床问题。迫切需要寻找新的 OA 疼痛状态的治疗方法。溴结构域和末端（BET）蛋白抑制剂在几种疼痛模型中具有强大的抗炎作用。然而，这些抑制剂在 OA 疼痛中的潜在机制尚未确定。因此，我们研究了 BET 抑制在 OA 疼痛大鼠模型中对疼痛相关行为的影响及其潜在机制。
通过向大鼠膝关节腔内注射单碘乙酸盐（MIA）建立 OA 模型。通过后肢负重不对称、机械性痛觉过敏和热痛觉超敏来评估大鼠的疼痛行为。在 MIA 诱导的 OA 疼痛模型中，在脊髓和背根神经节（DRG）中探讨了 BET 抑制的可能机制。
用 JQ1 或 MS417 抑制溴结构域蛋白 4（Brd4），或使用 AAV2/9-shRNA-Brd4-EGFP 介导的 Brd4 基因敲低，显著减轻了 MIA 诱导的疼痛行为。Brd4 抑制抑制了 MIA 诱导的 OA 疼痛大鼠脊髓和 DRG 中的 NF-κB 和 NF-κB 介导的炎症细胞因子。Brd4 抑制还减轻了氧化应激，并促进了我们的 MIA 诱导的 OA 疼痛模型中脊髓和 DRG 中核因子红细胞 2 相关因子 2（Nrf2）依赖性抗氧化基因。
总之，Brd4 抑制通过抑制神经炎症和激活 Nrf2 介导的抗氧化信号通路，减轻了 MIA 诱导的 OA 疼痛。虽然我们的模型不能完全代表 OA 在人类中的发展方式，但 Brd4 的抑制可能为 OA 疼痛的可能治疗提供新的见解。
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