Sanchez Christelle, Zappia Jérémie, Lambert Cécile, Foguenne Jacques, Dierckxsens Yvan, Dubuc Jean-Emile, Delcour Jean-Pierre, Gothot André, Henrotin Yves
MusculoSKeletal Innovative Research Lab, Center for Interdisciplinary Research on Medicines, University of Liège, Liège, Belgium.
Center for Interdisciplinary Research on Medicines, University of Liège, Liege, Belgium.
Front Pharmacol. 2022 Aug 11;13:931914. doi: 10.3389/fphar.2022.931914. eCollection 2022.
(CL) and (BS) extracts are used to relieve osteoarthritis symptoms. The aim of this study was to investigate their mechanisms of action at therapeutic plasmatic concentrations on primary human osteoarthritic (OA) chondrocytes. BS (10-50 μg/ml) and CL (0.4-2 μg/ml corresponding to 1-5 µM of curcumin) were evaluated separately or in combination on primary chondrocytes isolated from 17 OA patients and cultured in alginate beads. Ten patients were used for RNA-sequencing analysis. Proteomic confirmation was performed either by immunoassays in the culture supernatant or by flow cytometry for cell surface markers after 72 h of treatment. Significant gene expression modifications were already observed after 6 h of treatment at the highest dose of CL (2 μg/ml) while BS was significantly effective only after 24 h of treatment irrespective of the concentration tested. The most over-expressed genes by CL were anti-oxidative, detoxifying, and cytoprotective genes involved in the pathway. Down-regulated genes were principally pro-inflammatory cytokines and chemokines. Inversely, BS anti-oxidant/detoxifying activities were related to the activation of and PPARα pathways. BS anti-inflammatory effects were associated with the increase in GDF15, decrease in cholesterol cell intake and fatty acid metabolism-involved genes, and down-regulation of Toll-like receptors (TLRs) activation. Similar to CL, BS down-regulated ADAMTS1, 5, and MMP3, 13 genes expression. The combination of both CL and BS was significantly more effective than CL or BS alone on many genes such as IL-6, CCL2, ADAMTS1, and 5. BS and CL have anti-oxidative, anti-inflammatory, and anti-catabolic activities, suggesting a protective effect of these extracts on cartilage. Even if they share some mechanism of action, the two extracts act mainly on distinct pathways, and with different time courses, justifying their association to treat osteoarthritis.
（CL）提取物和（BS）提取物用于缓解骨关节炎症状。本研究的目的是研究它们在治疗血浆浓度下对原代人骨关节炎（OA）软骨细胞的作用机制。分别或联合评估了从17例OA患者分离并培养在藻酸盐珠中的原代软骨细胞上的BS（10 - 50μg/ml）和CL（0.4 - 2μg/ml，相当于1 - 5μM姜黄素）。10例患者用于RNA测序分析。处理72小时后，通过培养上清液中的免疫测定或细胞表面标志物的流式细胞术进行蛋白质组学确认。在CL最高剂量（2μg/ml）处理6小时后已观察到显著的基因表达改变，而BS无论测试浓度如何，仅在处理24小时后才显著有效。CL过度表达最多的基因是参与该途径的抗氧化、解毒和细胞保护基因。下调的基因主要是促炎细胞因子和趋化因子。相反，BS的抗氧化/解毒活性与和PPARα途径的激活有关。BS的抗炎作用与GDF15的增加、胆固醇细胞摄取和脂肪酸代谢相关基因的减少以及Toll样受体（TLRs）激活的下调有关。与CL相似，BS下调了ADAMTS1、5以及MMP3、13基因的表达。CL和BS的组合在许多基因如IL - 6、CCL2、ADAMTS1和5上比单独使用CL或BS显著更有效。BS和CL具有抗氧化、抗炎和抗分解代谢活性，表明这些提取物对软骨有保护作用。即使它们有一些共同的作用机制，但两种提取物主要作用于不同的途径，且时间进程不同，这证明了它们联合治疗骨关节炎的合理性。
