The natural product salicin alleviates osteoarthritis progression by binding to IRE1α and inhibiting endoplasmic reticulum stress through the IRE1α-IκBα-p65 signaling pathway.
The natural product salicin alleviates osteoarthritis progression by binding to IRE1α and inhibiting endoplasmic reticulum stress through the IRE1α-IκBα-p65 signaling pathway.
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DOI：
10.1038/s12276-022-00879-w
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发表时间：
2022-11
影响因子：
12.8
通讯作者：
Huang, Wei
中科院分区：
文献类型：
--
作者：
Zhu, Zhenglin;Gao, Shengqiang;Chen, Cheng;Xu, Wei;Xiao, Pengcheng;Chen, Zhiyu;Du, Chengcheng;Chen, Bowen;Gao, Yan;Wang, Chunli;Liao, Junyi;Huang, Wei
尽管骨关节炎 (OA) 在老年人群中发病率很高，但仍缺乏缓解 OA 疾病的药物 (DMOAD)。本研究旨在探讨小分子药物水杨苷 (SA) 对 OA 进展的影响和机制。用 TNF-α 刺激原代大鼠软骨细胞，并用或不用 SA 处理。在mRNA和蛋白水平上检测炎症因子、软骨基质变性标志物、细胞增殖和凋亡标志物。通过 EdU 测定或流式细胞术分析评估细胞增殖和凋亡。 RNA测序、分子对接和药物亲和力响应靶点稳定性分析被用来阐明其机制。采用大鼠OA模型评价关节内注射SA对OA进展的影响。我们发现SA可以挽救TNF-α诱导的软骨基质变性、抑制软骨细胞增殖并促进软骨细胞凋亡。从机制上讲，SA直接与IRE1α结合并占据IRE1α磷酸化位点，阻止IRE1α磷酸化并通过IRE1α-IκBα-p65信号传导调节IRE1α介导的内质网（ER）应激。最后，关节内注射负载 SA 的乳酸-乙醇酸 (PLGA) 通过抑制 OA 模型中 IRE1α 介导的 ER 应激来改善 OA 进展。总之，SA 通过直接与 ER 应激调节因子 IRE1α 结合来缓解 OA，并通过 IRE1α-IκBα-p65 信号传导抑制 IRE1α 介导的 ER 应激。局部使用小分子药物 SA 显示出改变 OA 进展的潜力。水杨素是一种从柳树皮中提取的小分子，可以为骨关节炎提供安全、有效的注射治疗，特别是在疾病的早期阶段。骨关节炎是由细胞内内质网 (ER) 的压力引起的，导致慢性炎症和软骨细胞（参与软骨形成的细胞）死亡。水杨苷口服后代谢为水杨酸，已成为阿司匹林和其他抗炎止痛药的基础，但其在骨关节炎中作用的确切机制尚不清楚。在细胞培养和大鼠实验中，中国重庆医科大学的 Junyi Liao、Wei Huang 及其同事展示了水杨苷如何直接与参与促进 ER 应激的蛋白质结合，从而阻断其活性。这反过来又防止了软骨基质的退化并提高了健康软骨细胞的水平。
Despite the high prevalence of osteoarthritis (OA) in older populations, disease-modifying OA drugs (DMOADs) are still lacking. This study was performed to investigate the effects and mechanisms of the small molecular drug salicin (SA) on OA progression. Primary rat chondrocytes were stimulated with TNF-α and treated with or without SA. Inflammatory factors, cartilage matrix degeneration markers, and cell proliferation and apoptosis markers were detected at the mRNA and protein levels. Cell proliferation and apoptosis were evaluated by EdU assays or flow cytometric analysis. RNA sequencing, molecular docking and drug affinity-responsive target stability analyses were used to clarify the mechanisms. The rat OA model was used to evaluate the effect of intra-articular injection of SA on OA progression. We found that SA rescued TNF-α-induced degeneration of the cartilage matrix, inhibition of chondrocyte proliferation, and promotion of chondrocyte apoptosis. Mechanistically, SA directly binds to IRE1α and occupies the IRE1α phosphorylation site, preventing IRE1α phosphorylation and regulating IRE1α-mediated endoplasmic reticulum (ER) stress by IRE1α-IκBα-p65 signaling. Finally, intra-articular injection of SA-loaded lactic-co-glycolic acid (PLGA) ameliorated OA progression by inhibiting IRE1α-mediated ER stress in the OA model. In conclusion, SA alleviates OA by directly binding to the ER stress regulator IRE1α and inhibits IRE1α-mediated ER stress via IRE1α-IκBα-p65 signaling. Topical use of the small molecular drug SA shows potential to modify OA progression. Salicin, a small molecule extracted from willow bark, could provide a safe, effective injectable treatment for osteoarthritis, particularly in the early stages of the disease. Osteoarthritis is driven by stress in the intracellular endoplasmic reticulum (ER), which results in chronic inflammation and death of chondrocytes, the cells involved in cartilage formation. Salicin, which is metabolized into salicylic acid after oral ingestion, already forms the basis of aspirin and other anti-inflammatory pain relievers, but the exact mechanisms of its action in osteoarthritis are unclear. In experiments on cell cultures and rats, Junyi Liao, Wei Huang and co-workers at Chongqing Medical University, Chongqing, China, showed how salicin binds directly to a protein involved in promoting ER stress, blocking its activity. This in turn prevented the degeneration of the cartilage matrix and boosted levels of healthy chondrocytes.
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