Aspirin reverses inflammatory suppression of chondrogenesis by stabilizing YAP.
Aspirin reverses inflammatory suppression of chondrogenesis by stabilizing YAP.
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阿司匹林通过稳定 YAP 逆转软骨形成的炎症抑制
DOI：
10.1111/cpr.13380
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发表时间：
2023-04
影响因子：
8.5
通讯作者：
中科院分区：
文献类型：
--
作者：
骨髓间充质干细胞（BMMSCs）移植方法是治疗骨关节炎（OA）的有希望的候选方法。然而，发生在细胞移植部位的炎症因子（如TNF‐α）是影响治疗效果的关键因素。先前的研究表明阿司匹林（AS）在干细胞分化中具有调节作用。然而，AS在骨髓间充质干细胞软骨形成中的作用知之甚少。本研究的目的是探讨AS对TNF - α对BMMSC软骨形成的负面影响的保护作用。在这项研究中，我们通过阿利新蓝染色、红啡素O - fast绿染色、血红素和伊红染色、免疫组织化学染色以及实时RT - PCR和western blot检测，研究了AS和TNF - α对BMMSCs软骨形成的影响。我们的研究结果表明，TNF‐α通过破坏软骨代谢平衡和促进BMMSCs的氧化应激来抑制BMMSCs的软骨分化，而AS治疗减弱了这些作用。此外，详细的分子机制分析表明，Yes相关蛋白（YAP）在这一过程中发挥了关键的调节作用。此外，AS治疗减轻了小鼠内侧半月板失稳（DMM）模型中软骨退变的进展。AS通过稳定YAP减轻TNF‐α对BMMSCs软骨形成的抑制作用，可能为OA治疗提供新的治疗策略。阿司匹林减轻小鼠DMM模型软骨退行性变的进展。(A)体内实验示意图。DMM手术后，小鼠注射阿司匹林或PBS 12周（每组10只）。(B) 12周后测量各组小鼠体重。(C)暴露于不同处理8周后小鼠左膝关节的代表性H&E和红花素O - fast绿色染色图像（每组n = 5）。(D)通过国际骨关节炎研究协会（OARSI）评分系统分析(C)中DMM手术后8周骨关节炎样表型的严重程度。(E)暴露于不同处理12周后小鼠左膝关节的代表性H&E和红花素O - fast绿色染色图像（每组n = 5）。(F)通过国际骨关节炎研究协会（OARSI）评分系统分析(E)中DMM手术后12周骨性关节炎样表型的严重程度。(G)不同处理8周后小鼠左膝关节软骨生成标志物（COL2A1和SOX9）和分解代谢标志物（MMP9和MMP13）的IHC染色。(H) (G)的免疫组化染色评分。(I)不同处理12周后小鼠左膝关节软骨生成标志物COL2A1、SOX9和分解代谢标志物MMP9、MMP13的免疫组化染色。(J)包含IHC染色分数(I)。* * * p < 0.05, p < 0.01, * * * p < 0.001。比例尺：0.5 mm （50×图）、250 μm （100×图）、100 μm （200×图）、50 μm （400×图）。
Bone marrow mesenchymal stem cells (BMMSCs) transplantation methods are promising candidates for osteoarthritis (OA) treatment. However, inflammatory factors (such as TNF‐α) that occur at cell transplantation sites are critical factors that impair the effectiveness of the treatment. Previous studies have shown that aspirin (AS) had a regulatory role in stem cell differentiation. However, little is known about the role of AS on the chondrogenesis of BMMSCs. The purpose of this study is to explore the protective role of AS against the negative effects of TNF‐α on BMMSC chondrogenesis. In this study, we investigated the effects of AS and TNF‐α on BMMSCs chondrogenesis by performing the Alcian Blue staining, safranin O‐fast green staining, haematoxylin and eosin staining, and immunohistochemical staining, as well as real‐time RT‐PCR and western blot assays. Our results demonstrated that TNF‐α inhibited chondrogenic differentiation of BMMSCs by disrupting the balance of cartilage metabolism and promoting oxidative stress in BMMSCs, while AS treatment attenuated these effects. Furthermore, a detailed molecular mechanistic analysis indicated that Yes‐associated protein (YAP) played a critical regulatory role in this process. In addition, AS treatment mitigated the progression of cartilage degeneration in a mouse destabilization of the medial meniscus (DMM) model. AS alleviated the inhibitory effect of TNF‐α on chondrogenesis of BMMSCs by stabilizing YAP, which may provide new therapeutic strategies for OA treatment. Aspirin mitigates the progression of cartilage degeneration in a mouse DMM model. (A) A schematic of the in vivo experiment. After DMM surgery, mice were injected with aspirin or PBS for 12 weeks (n = 10 per group). (B) The body weights of mice from different treatment groups were measured after 12 weeks. (C) Representative H&E and safranin O‐fast green staining images of the left knee joint of mice after exposure to different treatments for 8 weeks (n = 5 per group). (D) The severity of the OA‐like phenotype 8 weeks after DMM surgery in (C) was analysed by the Osteoarthritis Research Society International (OARSI) score system. (E) Representative H&E and safranin O‐fast green staining images of the left knee joint of mice after exposure to different treatments for 12 weeks (n = 5 per group). (F) The severity of the OA‐like phenotype 12 weeks after DMM surgery in (E) was analysed by the Osteoarthritis Research Society International (OARSI) score system. (G) IHC staining of chondrogenic markers (COL2A1 and SOX9) and catabolic markers (MMP9 and MMP13) in the left knee joint of mice after different treatments for 8 weeks. (H) IHC staining scores of (G). (I) IHC staining of chondrogenic markers (COL2A1 and SOX9) and catabolic markers (MMP9 and MMP13) in the left knee joint of mice after different treatments for 12 weeks. (J) IHC staining scores of (I). *p < 0.05, **p < 0.01, ***p < 0.001. Scale bars: 0.5 mm (50× figures), 250 μm (100× figures), 100 μm (200× figures), 50 μm (400× figures).
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影响因子：
3
作者：
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通讯作者：
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影响因子：
8.1
作者：
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影响因子：
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影响因子：
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作者：
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