National Innovation and Attracting Talents "111" base, Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400030, China.
School of Mathematics and Information Engineering, Chongqing University of Education, Chongqing, 400065, China.
Inflammation. 2020 Oct;43(5):1742-1750. doi: 10.1007/s10753-020-01248-3.
Osteoarthritis (OA) is a chronic degenerative joint disease which is greatly affected by the inflammatory response triggered by the NF-κB signaling pathway. Alpinetin (APT) is a natural flavonoid compound, which has been reported to have many important biological activities such as antibacterial, antitumor, and anti-inflammatory. However, the action of its effect on chondrocytes in OA has yet to be elucidated. In this study, we investigated APT's anti-inflammatory action. The effects of APT on cell viability and cytotoxicity of rat chondrocytes was investigated by CCK8. Western blotting, qRT-PCR, and immunofluorescent staining were used to elucidate the molecular mechanisms and signaling pathways of APT mediating anti-inflammatory effects on chondrocytes. An OA model was induced by destabilization of the medial meniscus (DMM) in rats, then APT was injected into the knee articular cavity to examine its anti-inflammatory effects in vivo. These results showed that APT could reduce the TNF-α-induced increase of MMP-13 and ADAMTS-5 and decrease of COL2A1 levels. APT antagonized TNF-α-induced down-regulation of BCL-2 and CDK1. Further studies have shown that APT simultaneously repressed cell nucleus translocation of p65 and the phosphorylation of IκB and activated the phosphorylation of ERK. In vivo, APT suppressed cartilage matrix degradation. In conclusion, APT appears to favorably modulate anti-inflammatory effects in chondrocytes making it a promising compound for OA treatment. Graphical Abstract Inhibitory effects of Alpinetin on TNF-α-induced NF-κB activation resulted in destruction of cartilage in rat OA chondrocytes in vitro. The TNF-α receptor were stimulated by TNF-α, activating the cytoplasmic IκBα kinases(IKKS), then IKKs will be phosphorylated, and subsequently degraded by the ubiquitin-proteasome system. NF-κB transfer to the nucleus and bind various NF-κB regulates the NF-κB recognition site in the promoter region. Which triggers the gene expression of pro-inflammatory and pro-apoptotic. However, Alpinetin could inhibits the NF-κB signaling pathway in different ways: APT inhibits IκBα phosphorylation, preventing phosphorylated ubiquitination of IκBα further. Moreover, APT blocks translocation of the activated NF-κB to the nucleus, to protect the cartilage tissue from damage.
骨关节炎（OA）是一种慢性退行性关节疾病，其受 NF-κB 信号通路触发的炎症反应的影响很大。白杨素（APT）是一种天然黄酮类化合物，已被报道具有许多重要的生物学活性，如抗菌、抗肿瘤和抗炎作用。然而，其对 OA 软骨细胞的作用尚不清楚。在这项研究中，我们研究了 APT 的抗炎作用。通过 CCK8 研究了 APT 对大鼠软骨细胞活力和细胞毒性的影响。通过 Western blot、qRT-PCR 和免疫荧光染色阐明了 APT 介导的抗炎作用对软骨细胞的分子机制和信号通路。通过内侧半月板不稳（DMM）在大鼠中诱导 OA 模型，然后将 APT 注入膝关节腔，在体内检查其抗炎作用。结果表明，APT 可降低 TNF-α 诱导的 MMP-13 和 ADAMTS-5 增加和 COL2A1 水平降低。APT 拮抗 TNF-α 诱导的 BCL-2 和 CDK1 下调。进一步的研究表明，APT 同时抑制 p65 的细胞核易位和 IκB 的磷酸化，并激活 ERK 的磷酸化。在体内，APT 抑制软骨基质降解。总之，APT 似乎有利于调节软骨细胞的抗炎作用，使其成为治疗 OA 的有前途的化合物。 图表摘要 APT 在体外抑制 TNF-α 诱导的 NF-κB 激活，导致大鼠 OA 软骨细胞的软骨破坏。TNF-α 受体被 TNF-α 刺激，激活细胞质 IκBα 激酶（IKK），然后 IKKs 被磷酸化，随后被泛素-蛋白酶体系统降解。NF-κB 转移到细胞核并结合各种 NF-κB 调节启动子区域中的 NF-κB 调节元件。这会触发促炎和促凋亡基因的表达。然而，APT 可以通过不同的方式抑制 NF-κB 信号通路：APT 抑制 IκBα 磷酸化，从而阻止磷酸化的 IκBα 进一步泛素化。此外，APT 阻止激活的 NF-κB 向细胞核易位，以保护软骨组织免受损伤。
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