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山东大学学报 (医学版) ›› 2025, Vol. 63 ›› Issue (7): 11-22.doi: 10.6040/j.issn.1671-7554.0.2025.0047

• 基础医学 • 上一篇    下一篇

木犀草素在炎症微环境下调控Wnt/β-catenin信号通路促进骨髓间充质干细胞成软骨分化的机制

赵灿斌1,邵将2,管东辉2,秦英3,丁强1,郭良1,王伟伟1,陈威1,闫小龙4,曾平5   

  1. 1.广西中医药大学第一临床医学院, 广西 南宁 530200;2.山东中医药大学附属医院骨科, 山东 济南 250014; 3.济南市长清区中医医院骨科, 山东 济南 250300;4.济南市长清区人民医院/山东中医药大学附属医院大学城医院, 山东 济南 250030;5.广西中医药大学第一附属医院骨二科, 广西 南宁 530200
  • 发布日期:2025-07-08
  • 通讯作者: 闫小龙. E-mail:yanxiaolong1986@163.com曾平. E-mail:zengp@gxtcmu.edu.cn
  • 基金资助:
    国家自然科学基金(82160913);山东省自然科学基金(ZR2022MH147)

Mechanism of luteolin regulating Wnt/β-catenin signal pathway in inflammatory microenvironment to promote chondrogenic differentiation of bone marrow mesenchymal stem cells

ZHAO Canbin1, SHAO Jiang2, GUAN Donghui2, QIN Ying3, DING Qiang1, GUO Liang1, WANG Weiwei1, CHEN Wei1, YAN Xiaolong4, ZENG Ping5   

  1. 1. First Clinical Medical College, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi, China;
    2. Department of Orthopedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong, China;
    3. Department of Orthopedics, Jinan Changqing District Traditional Chinese Medicine Hospital, Jinan 250300, Shandong, China;
    4. Orthopedics Department, Jinan Changqing District Peoples Hospital/University Town Hospital, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250300, Shandong, China;
    5. Department of Orthopedics 2, First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530200, Guangxi, China
  • Published:2025-07-08

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摘要： 目的 探讨炎症微环境作用下木犀草素对骨髓间充质干细胞(bone marrow mesenchymal stem cells, BMSCs)成软骨分化以及对Wnt/β-catenin信号通路的影响。 方法 通过网络药理学手段筛选木犀草素调控成软骨分化的基因集,并绘制蛋白质互相作用(protrin-protein interaction, PPI)网络图,随后进行基因本体论(gene ontology, GO)及京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes, KEGG)富集分析,筛选成软骨分化相关靶基因与木犀草素进行分子对接处理。采用细胞计数试剂盒-8(cell counting kit-8, CCK8)及细胞增殖试验检测木犀草素对BMSCs的细胞毒性。将大鼠BMSCs分为对照组(使用2 mL成软骨分化诱导培养基培养)、模型组［使用2 mL含10 ng/mL肿瘤坏死因子(tumor necrosis factor-α, TNF-α)的成软骨分化诱导培养基构建炎症微环境］、低剂量组(在模型组的基础上加入5 μmol木犀草素干预)及高剂量组(在模型组的基础上加入10 μmol木犀草素干预),诱导各组细胞成软骨分化,构建微团软骨细胞球。对微团软骨细胞球包埋切片后进行组织学(番红-固绿、甲苯胺蓝、阿利新蓝)染色,采用RT-qPCR法检测各组软骨细胞球成软骨基因Ⅱ型胶原蛋白(collagen type Ⅱ, COL2)、 Sry相关HMG框转录因子9(sry-box transcription factor 9, SOX9)、聚集蛋白聚糖(aggrecan, ACAN)表达量及Wnt/β-catenin信号通路蛋白激酶A(protein kinase A, PKA)、环磷腺苷效应元件结合蛋白(cAMP response element-binding protein, CBP)、糖原合成酶激酶3β(glycogen synthase kinase 3 bate, GSK3β)、β-连环蛋白(beta-catenin, β-CATENIN)、细胞髓细胞瘤病毒癌基因同源物(cellular myelocytomatosis viral oncogene homolog, c-MYC)、细胞周期蛋白D1(Cyclin D1)表达量,采用Western blotting 法检测Wnt/β-catenin信号通路蛋白PKA、CBP、GSK3β、β-CATENIN、c-MYC、Cyclin D1表达量。 结果 共筛选出木犀草素调控成软骨分化靶基因54个,其中53个参与PPI网络图的构建。靶基因涉及Wnt/β-catenin信号通路正向调控及负向调控等生物过程,木犀草素与Ⅱ型胶原α1蛋白(collagen type Ⅱ alpha 1chain, COL2A1)、SOX9、ACAN 均可良好对接。5 μmol、10 μmol木犀草素无明显细胞毒性。组织学染色显示,模型组软骨细胞球染色比对照组稀疏而且无序,加入木犀草素干预后被明显逆转。与对照组相比,模型组软骨细胞球中COL2、SOX9、ACAN、PKA、CBP、GSK3β、β-CATENIN、c-MC、CYCLIN D1的mRNA表达量明显降低(P<0.05),GSK3β表达量明显升高(P<0.05),Wnt/β-catenin信号通路蛋白PKA、CBP、β-CATENIN、c-MYC、CYCLIN D1表达量明显降低(P<0.05),GSK3β表达量明显升高(P<0.05),加入木犀草素干预后被显著逆转。 结论 在炎症微环境下,木犀草素可促进BMSCs成软骨分化,可能与激活Wnt/β-catenin信号通路有关。

关键词: 木犀草素, 骨髓间充质干细胞, 成软骨分化, 炎症微环境, Wnt/β-catenin信号通路

Abstract: Objective To investigate the effect of luteolin on chondrogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)and the Wnt/β-catenin signaling pathway in an inflammatory microenvironment. Methods Network pharmacology was used to screen gene sets regulated by luteolin for chondrogenic differentiation, and a protein-protein interaction(PPI)network was constructed. Gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)enrichment analyses were performed to screen chondrogenic differentiation-related target genes, which were then subjected to molecular docking with luteolin. The cytotoxicity of luteolin on BMSCs was determined using the cell counting kit-8(CCK8)and cell proliferation assay. Rat BMSCs were divided into control group(caltured with 2 mL chondrogenic differentiation induction medium), model group ［using 2 mL of chondrogenic differentiation induction medium containing 10 ng/mL tumor necrosis factor-α(TNF-α)to construct an inflammatory microenvironment］, low-dose group(5 μmol luteolin intervention based on the model group), and high-dose group(10 μmol luteolin intervention based on the model group). Chondrogenic differentiation was induced in each group to construct micromass cartilage pellets. After embedding and sectioning, histologic staining(Safranin-O/Fast Green, Toluidine Blue, Alcian Blue)was performed. RT-qPCR was used to detect the expression of chondrogenic genes collagen type Ⅱ(COL2), Sry-box transcription factor 9(SOX9), and aggrecan(ACAN), as well as the expression of Wnt/β-catenin signaling pathway proteins including protein kinase A(PKA), cAMP response element-binding protein(CBP), glycogen synthase kinase 3β(GSK3β), β-catenin(β-CATENIN), cellular myelocytomatosis viral oncogene homolog(c-MYC), and Cyclin D1. Western blotting was used to determine the protein expression levels of these signaling molecules. Results A total of 54 target genes regulated by luteolin for chondrogenic differentiation were screened, 53 of which were involved in the construction of the PPI network. The target genes were associated with biological processes, including positive and negative regulation of the Wnt/β-catenin signaling pathway. Luteolin showed good docking with collagen type Ⅱ alpha 1 chain(COL2A1), SOX9 and ACAN. Luteolin at 5 μmol and 10 μmol showed no significant cytotoxicity. Histological staining revealed that the model group had sparser and more disorganized staining in cartilage pellets compared to the control group, which was significantly reversed by luteolin intervention. Compared with the control group, the model group had significantly lower mRNA expression of COL2, SOX9, ACAN, PKA, CBP, β-CATENIN, c-MYC, and Cyclin D1(P<0.05), while GSK3β expression was significantly higher(P<0.05). Protein expression levels of PKA, CBP, β-CATENIN, c-MYC, and Cyclin D1 in the Wnt/β-catenin pathway were significantly decreased(P<0.05), and GSK3β was increased(P<0.05)in the model group, all of which were significantly reversed by luteolin intervention. Conclusion Luteolin promotes chondrogenic differentiation of BMSCs in an inflammatory microenvironment, possibly by activating the Wnt/β-catenin signaling pathway.

Key words: Luteolin, Bone marrow mesenchymal stem cells, Chondrogenic differentiation, Inflammatory microenvironment, Wnt/β-catenin signaling pathway

中图分类号: 

  • R274
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