P53对基于MRI的骨关节炎间隙狭窄程度影响的临床研究Clinical study of the effect of P53 on the degree of osteoarthritis space stenosis based on magnetic resonance imaging
张双;信瑞强;石逸杰;李艳翠;彭如臣;
摘要(Abstract):
目的 利用生物信息学技术对骨关节炎(osteoarthritis,OA)差异表达基因进行识别和功能富集分析,并通过临床数据研究P53对基于MRI的OA间隙狭窄程度的影响。材料与方法 下载微阵列数据(GSE55235),利用GEO2R鉴别OA患者与正常滑膜样本间的差异表达基因(differentially expressed genes,DEGs)。利用基因本体论(gene ontology,GO)和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)对差异表达基因进行基因富集分析,进一步构建蛋白—蛋白互作(protein-protein interaction,PPI)网络分析,识别重要模块,鉴定核心基因。选取50例OA间隙狭窄患者,利用MRI检测其骨关节情况,分析其临床资料,运用Pearson卡方检验、Spearman相关性分析和多因素Logistic回归进行统计学分析。结果 对照组与OA组滑膜组织之间存在差异。GSE55235的分析结果识别出91个差异表达基因。DEGs集富集分析全面概述了OA的一些主要病理生理机制:细胞对过氧化氢的反应、P53信号通路。鉴定出了4个关键基因:MMP1、CXCL8、VEGFA和JUN。与正常组对比,MMP1在OA组中高表达,CXCL8、VEGFA和JUN在OA组中低表达。Pearson卡方检验、Spearman相关性分析和多因素Logistic回归结果显示P53与OA间隙狭窄程度显著相关(OR=0.112,95%CI:0.025~0.495,P=0.004),而性别、年龄、MMP1、VEGFA、CXCL8与OA间隙狭窄程度无显著相关性(P值均大于0.05)。结论 基于MRI结果的基础上,判断细胞对过氧化氢的反应、P53信号通路能为OA的诊断和治疗提供新的研究靶点。P53在OA患者中低表达,可能作为其潜在治疗靶点。MRI也有利于OA患者早期的诊断与治疗,降低OA发病率。
关键词(KeyWords): 磁共振成像;骨关节炎;生物信息学;差异表达基因;富集分析;P53信号通路
基金项目(Foundation):
作者(Authors): 张双;信瑞强;石逸杰;李艳翠;彭如臣;
参考文献(References):
- [1]Ghouri A,Conaghan PG.Prospects for therapies in osteoarthritis[J].Calcif Tissue Int,2021,109(3):339-350.DOI:10.1007/s00223-020-00672-9.
- [2]Hunter DJ,Bierma-Zeinstra S.Osteoarthritis[J].Lancet,2019,393(10182):1745-1759.DOI:10.1016/S0140-6736(19)30417-9.
- [3]Silverwood V,Blagojevic-Bucknall M,Jinks C,et al.Current evidence on risk factors for knee osteoarthritis in older adults:a systematic review and meta-analysis[J].Osteoarthritis Cartilage,2015,23(4):507-515.DOI:10.1016/j.joca.2014.11.019.
- [4]Wang F,Shi WX,Chen J,et al.Clinical therapeutic effects of combined diacerein and glucosamine in the treatment of osteoarthritis:a protocol for systematic review and meta-analysis[J].Medicine(Baltimore),2021,100(47):e27583.DOI:10.1097/MD.0000000000027583.
- [5]Martel-Pelletier J,Tardif G,Paiement P,et al.Common biochemical and magnetic resonance imaging biomarkers of early knee osteoarthritis and of exercise/training in athletes:a narrative review[J/OL].Diagnostics (Basel),2021,11(8)[2022-04-07].https://www.mdpi.com/2075-4418/11/8/1488/htm.DOI:10.3390/diagnostics11081488.
- [6]Ota S,Sasaki E,Sasaki S,et al.Relationship between abnormalities detected by magnetic resonance imaging and knee symptoms in early knee osteoarthritis[J/OL].Sci Rep,2021,11(1)[2022-04-07].https://www.nature.com/articles/s41598-021-94382-3.DOI:10.1038/s41598-021-94382-3.
- [7]van Meurs JBJ.Osteoarthritis year in review 2016:genetics,genomics and epigenetics[J].Osteoarthr Cartil,2017,25(2):181-189.DOI:10.1016/j.joca.2016.11.011.
- [8]Meyer F,Dittmann A,Kornak U,et al.Chondrocytes from osteoarthritic and chondrocalcinosis cartilage represent different phenotypes[J/OL].Front Cell Dev Biol,2021,9[2022-04-07].https://www.frontiersin.org/articles/10.3389/fcell.2021.622287/full.DOI:10.3389/fcell.2021.622287.
- [9]Lee MC,Saleh R,Achuthan A,et al.CCL17 blockade as a therapy for osteoarthritis pain and disease[J/OL].Arthritis Res Ther,2018,20(1)[2022-04-07].https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-018-1560-9.DOI:10.1186/s13075-018-1560-9.
- [10]Nelson AE,Allen KD,Golightly YM,et al.A systematic review of recommendations and guidelines for the management of osteoarthritis:the chronic osteoarthritis management initiative of the US bone and joint initiative[J].Semin Arthritis Rheum,2014,43(6):701-712.DOI:10.1016/j.semarthrit.2013.11.012.
- [11]Zheng LL,Chen WS,Xian GY,et al.Identification of abnormally methylated-differentially expressed genes and pathways in osteoarthritis:a comprehensive bioinformatic study[J].Clin Rheumatol,2021,40(8):3247-3256.DOI:10.1007/s10067-020-05539-w.
- [12]Guo SY,Huang ZH,Liu XK,et al.Biodata mining of differentially expressed genes between acute myocardial infarction and unstable angina based on integrated bioinformatics[J/OL].Biomed Res Int,2021,2021[2022-04-07].https://www.hindawi.com/journals/bmri/2021/5584681/.DOI:10.1155/2021/5584681.
- [13]Fang LJ,Tang TY,Hu MQ.Identification of differentially expressed genes in COVID-19 and integrated bioinformatics analysis of signaling pathways[J/OL].Genet Res (Camb),2021,2021[2022-04-07].https://www.hindawi.com/journals/gr/2021/2728757/.DOI:10.1155/2021/2728757.
- [14]Wang JC,Sun YS,Liu JY,et al.Roles of long non-coding RNA in osteoarthritis (review)[J/OL].Int J Mol Med,2021,48(1)[2022-04-07].https://www.spandidos-publications.com/10.3892/ijmm.2021.4966.DOI:10.3892/ijmm.2021.4966.
- [15]Hunter DJ,Guermazi A,Lo GH,et al.Evolution of semi-quantitative whole joint assessment of knee OA:MOAKS (MRI Osteoarthritis Knee Score)[J].Osteoarthritis Cartilage,2011,19(8):990-1002.DOI:10.1016/j.joca.2011.05.004.
- [16]Takaoka R,Yatani H,Senzaki Y,et al.Relative risk of positional and dynamic temporomandibular disc abnormality for osteoarthritis-magnetic resonance imaging study[J].J Oral Rehabil,2021,48(4):375-383.DOI:10.1111/joor.13138.
- [17]Munteanu SE,Auhl M,Tan JM,et al.Characterisation of first metatarsophalangeal joint osteoarthritis using magnetic resonance imaging[J].Clin Rheumatol,2021,40(12):5067-5076.DOI:10.1007/s10067-021-05849-7.
- [18]Guo H,Wang YQ,Qiu LH,et al.Structural and functional abnormalities in knee osteoarthritis pain revealed with multimodal magnetic resonance imaging[J/OL].Front Hum Neurosci,2021,15[2022-04-07].https://www.frontiersin.org/articles/10.3389/fnhum.2021.783355/full.DOI:10.3389/fnhum.2021.783355.
- [19]Selvaraj EA,Mózes FE,Jayaswal ANA,et al.Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD:a systematic review and meta-analysis[J].J Hepatol,2021,75(4):770-785.DOI:10.1016/j.jhep.2021.04.044.
- [20]van Beest S,Kroon HM,Reijnierse M,et al.Two-year changes in magnetic resonance imaging features and pain in thumb base osteoarthritis[J].Arthritis Care Res (Hoboken),2021,73(11):1628-1637.DOI:10.1002/acr.24355.
- [21]Tiku ML,Shah R,Allison GT.Evidence linking chondrocyte lipid peroxidation to cartilage matrix protein degradation.Possible role in cartilage aging and the pathogenesis of osteoarthritis[J].J Biol Chem,2000,275(26):20069-20076.DOI:10.1074/jbc.M907604199.
- [22]Jovanovic DV,Mineau F,Notoya K,et al.Nitric oxide induced cell death in human osteoarthritic synoviocytes is mediated by tyrosine kinase activation and hydrogen peroxide and/or superoxide formation[J].J Rheumatol,2002,29(10):2165-2175.
- [23]Khan IM,Gilbert SJ,Caterson B,et al.Oxidative stress induces expression of osteoarthritis markers procollagen IIA and 3B3 (-) in adult bovine articular cartilage[J].Osteoarthritis Cartilage,2008,16(6):698-707.DOI:10.1016/j.joca.2007.10.004.
- [24]Goutas A,Syrrou C,Papathanasiou I,et al.The autophagic response to oxidative stress in osteoarthritic chondrocytes is deregulated[J].Free Radic Biol Med,2018,126:122-132.DOI:10.1016/j.freeradbiomed.2018.08.003.
- [25]Slattery ML,Mullany LE,Wolff RK,et al.The p53-signaling pathway and colorectal cancer:interactions between downstream p53 target genes and mi RNAs[J].Genomics,2019,111(4):762-771.DOI:10.1016/j.ygeno.2018.05.006.
- [26]Yang HW,Chung M,Kudo T,et al.Competing memories of mitogen and p53 signalling control cell-cycle entry[J].Nature,2017,549(7672):404-408.DOI:10.1038/nature23880.
- [27]Seemayer CA,Kuchen S,Neidhart M,et al.p53 in rheumatoid arthritis synovial fibroblasts at sites of invasion[J].Ann Rheum Dis,2003,62(12):1139-1144.DOI:10.1136/ard.2003.007401.
- [28]Yan SJ,Wang M,Zhao J,et al.micro RNA-34a affects chondrocyte apoptosis and proliferation by targeting the SIRT1/p53 signaling pathway during the pathogenesis of osteoarthritis[J].Int J Mol Med,2016,38(1):201-209.DOI:10.3892/ijmm.2016.2618.
- [29]Yang ZM,Tang YX,Lu HD,et al.Long non-coding RNAreprogramming (lnc RNA-ROR) regulates cell apoptosis and autophagy in chondrocytes[J].J Cell Biochem,2018,119(10):8432-8440.DOI:10.1002/jcb.27057.
- [30]Chiou CS,Wu CM,Dubey NK,et al.Mechanistic insight into hyaluronic acid and platelet-rich plasma-mediated anti-inflammatory and anti-apoptotic activities in osteoarthritic mice[J].Aging,2018,10(12):4152-4165.DOI:10.18632/aging.101713.
- [31]Li SJ,Ma FB,Pang XC,et al.Synthesis of chondroitin sulfate magnesium for osteoarthritis treatment[J].Carbohydr Polym,2019,212:387-394.DOI:10.1016/j.carbpol.2019.02.061.
- [32]Xu LJ,Liu CC,Chen LM,et al.Reduction of SIRT1 mediates monosodium iodoacetate-induced osteoarthritic pain by upregulating p53 expression in rats[J].Pain Physician,2021,24(7):E1025-E1035.
- [33]Li WJ,Xiong Y,Chen WP,et al.Wnt/β-catenin signaling may induce senescence of chondrocytes in osteoarthritis[J].Exp Ther Med,2020,20(3):2631-2638.DOI:10.3892/etm.2020.9022.
- [34]Jiang WJ,Wang XY,Su SW,et al.Identifying the shared genes and KEGG pathways of Resolvin D1-targeted network and osteoarthritis using bioinformatics[J].Bioengineered,2022,13(4):9839-9854.DOI:10.1080/21655979.2022.2061288.