The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China.
J Orthop Surg Res. 2023 Apr 22;18(1):312. doi: 10.1186/s13018-023-03761-1.
Although fisetin may exist widely in many natural herbs, its anti-OP mechanism is still unclear. The aim of this study is to explore the molecular anti-osteoporosis (OP) mechanism of fisetin based on network pharmacology and cell experiments.
The target of fisetin was extracted by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The targets of OP were obtained by DisGeNET, GeneCards and the Comparative Toxicogenomics Database, and the targets of fisetin in OP were screened by cross-analysis. The protein-protein interaction (PPI) network was constructed by STRING, and the core targets were obtained. We performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses on common targets via the Database for Annotation, Visualization and Integrated Discovery. Finally, an in vitro cell experiment was used to verify the anti-OP effect and mechanism of fisetin.
There are 44 targets of fisetin related to the treatment of OP. The PPI results suggest that CTNNB1, CCND1, TP53, JUN, and AKT1 are the core targets. A total of 259 biological process, 57 molecular function and 26 cell component terms were obtained from GO enrichment analysis. The results of KEGG pathway enrichment analysis suggested that fisetin treatment of OP may be related to the Wnt signaling pathway, estrogen signaling pathway, PI3K-Akt signaling pathway and other signaling pathways. In vitro cell experiments showed that fisetin significantly increased the expression levels of ALP, collagen I, osteopontin and RUNX2 in bone marrow mesenchymal stem cells (BMSCs) (p < 0.05). Fisetin also increased the gene expression levels of Wnt3 and β-catenin (CTNNB1) in BMSCs, which indicates that fisetin can regulate the Wnt/β-catenin signaling pathway and promote the osteogenic differentiation of BMSCs.
Fisetin acts on multiple targets and pathways in the treatment of OP; mechanistically, it regulates the Wnt/β-catenin signaling pathway, which promotes the osteogenic differentiation of BMSCs and maintains bone homeostasis. The results of this study provide a theoretical basis for further study on the complex anti-OP mechanism of fisetin.
尽管漆黄素广泛存在于许多天然草药中，但它的抗骨质疏松（OP）机制尚不清楚。本研究旨在基于网络药理学和细胞实验探讨漆黄素的分子抗骨质疏松（OP）机制。
通过中药系统药理学数据库和分析平台（TCMSP）提取漆黄素的靶点。通过 DisGeNET、GeneCards 和比较毒理学基因组学数据库获得 OP 靶点，并通过交叉分析筛选漆黄素治疗 OP 的靶点。通过 STRING 构建蛋白质-蛋白质相互作用（PPI）网络，并获得核心靶点。通过数据库 for Annotation、Visualization and Integrated Discovery（DAVID）对共同靶点进行基因本体（GO）和京都基因与基因组百科全书（KEGG）通路富集分析。最后，进行体外细胞实验验证漆黄素的抗 OP 作用及其机制。
漆黄素治疗 OP 相关靶点共 44 个。PPI 结果提示 CTNNB1、CCND1、TP53、JUN 和 AKT1 是核心靶点。GO 富集分析共获得 259 个生物过程、57 个分子功能和 26 个细胞成分术语。KEGG 通路富集分析结果提示，漆黄素治疗 OP 可能与 Wnt 信号通路、雌激素信号通路、PI3K-Akt 信号通路等信号通路有关。体外细胞实验表明，漆黄素可显著增加骨髓间充质干细胞（BMSCs）中碱性磷酸酶（ALP）、Ⅰ型胶原（collagen I）、骨桥蛋白（osteopontin）和 runt 相关转录因子 2（RUNX2）的表达水平（p<0.05）。漆黄素还增加了 BMSCs 中 Wnt3 和 β-连环蛋白（CTNNB1）的基因表达水平，表明漆黄素可以调节 Wnt/β-连环蛋白信号通路，促进 BMSCs 的成骨分化。
漆黄素通过多靶点、多通路发挥治疗 OP 的作用；其机制可能是通过调节 Wnt/β-连环蛋白信号通路，促进 BMSCs 的成骨分化，维持骨稳态。本研究为进一步研究漆黄素复杂的抗 OP 机制提供了理论依据。
