张浩 赵琦 李晓强 黄昊 李奕廷 刘佳

【摘要】 目的 基于网络药理学探究PP2对骨性关节炎（OA）的潜在治疗作用及具体机制。方法 从PharmMappe和Swiss target prediction在线数据库中收集PP2靶点，而致病性OA靶点则从GeneCards databases、Online Mendelian Inheritance in Man（OMIM）、PharmGkb、Therapeutic Target Database（TTD）、DrugBank 5个在线数据库中获得。通过VENNY在线工具找出PP2和OA的交集基因，通过基因分类学（gene ontology，GO）、京都基因和基因组百科全书 （Kyoto encyclopedia of genes and genomes，KEGG）富集分析，预测与PP2相关的潜在功能和信号通路。构建PP2的蛋白互作网络，以筛选出PP2的核心基因。通过分子对接模拟研究验证预测；通过大鼠软骨细胞中加不同浓度PP2（0，20 μM），然后进行qRT-PCR对差异基因进行验证。结果 PP2中的活性成分221个，与疾病共同靶基因为67个，其中筛选出核心靶基因15个。GO富集和KEGG通路富集中涉及MAPK信号通路、EGFR信号通路、PI3K-Akt信号通路、Ras信号通路、Rap1信号通路、JAK-STAT信号通路、AGE-RAGE信号通路和ErbB信号通路等多种信号通路。结论 PP2能够调节多种信号通路从而达到治疗OA的作用。其中mTOR、EGFR、SRC、MAPK8、PIK3CA、MAPK14、SDHA、EGF、CREBBP JAK1、CSNK2A2、ERBB2、PDGFRA、KIT和SOD2基因是值得关注的靶基因。MAPK信号通路和PI3K-Akt信号通路是主要调控通路。

【关键词】 骨性关节炎；网络药理学；PP2；MAPK信号通路；PI3K-Akt信号通路

中圖分类号：R684.3 文献标志码：A DOI：10.3969/j.issn.1003-1383.2023.05.004

【Abstract】 Objective To explore the potential therapeutic effect and mechanism of PP2 on osteoarthritis （OA） based on network pharmacology.Methods PP2 targets were collected from PharmMappe and Swiss target prediction online databases. However， pathogenic OA targets were obtained from 5 online databases， namely， GeneCards databases， Online Mendelian Inheritance in Man （OMIM）， PharmGkb， Therapeutic Target Database （TTD） and DrugBank online databases. The intersection genes of PP2 and OA were found by VENNY online tool. And then， the potential functions and signal pathways related to PP2 were predicted by gene ontology （GO） and Kyoto encyclopedia of genes and genomes （KEGG） enrichment analysis. The protein interaction network of PP2 was constructed to screen the core genes of PP2. Then， the prediction was verified by molecular docking simulation. Different concentrations of PP2 （0， 20 μM） were added to rat chondrocytes， and then the differential genes were confirmed by qRT-PCR.Results There were 221 active components in PP2， and 67 shared common target genes with the disease， of which 15 core target genes were screened. GO enrichment and KFGG pathway enrichment involved many signal pathways， such as MAPK signal pathway， EGFR signal pathway， PI3K-Akt signal pathway， Ras signal pathway， Rap1 signal pathway， JAK-STAT signal pathway， AGE-RAGE signal pathway and ErbB signal pathway， etc.Conclusion PP2 can regulate various signal pathways to achieve therapeutic effects on OA. mTOR， EGFR， SRC， MAPK8， PIK3CA， MAPK14， SDHA， EGF， CREBBP JAK1， CSNK2A2， ERBB2， PDGFRA， KIT and SOD2 genes are target genes which are worthy of attention. MAPK signalling pathway and PI3K-Akt signalling pathway are main regulatory pathways.

【Key words】 osteoarthritis （OA）; network pharmacology; PP2; MAPK signaling pathway; PI3K-Akt signaling pathway

骨性关节炎（osteoarthritis，OA）是一种能够严重影响患者生活质量的慢性退行性关节疾病，多见于中老年人，并随年龄增长其发病率也呈增长趋势［1］。尽管我们已经知道，在OA的发生发展过程中，多种因素对其有影响，如遗传、代谢、环境和创伤等［2］，但其具体的发病分子机制尚未有明确的阐述。近年来研究人员对OA发病的具体机制研究越来越多［3］，认为在OA的不同发病阶段可能存在多种致病机制［4］，但到目前为止还未找到有效的疾病治疗方法。……