基于GEO数据库对骨关节炎滑膜差异基因的筛选及生物信息学分析
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摘要
目的:利用生物信息学对骨关节炎与正常关节滑膜间差异基因进行分析,探索骨关节炎的发病机制。方法:从GEO数据库下载关节滑膜基因芯片数据库,利用GEO2R筛选出差异基因,DAVID 6.7数据库对差异基因进行功能GO分析及KEGG信号通路分析,String-db数据库构建蛋白之间的相互作用网络图(PPI),并采用Cytoscape 3.6.1软件获取关键靶基因。结果:GEO2R共筛选出差异基因490个,包含上调基因61个,下调基因429个,其主要涉及细胞分化、细胞生长、骨骼肌器官发育、cAMP反应等生理过程,且主要富集在细胞外基质受体互作、近端肾小管重吸收碳酸氢盐、胃酸分泌、催产素、环磷酸腺苷/蛋白激酶G、脂肪细胞因子信号通路中。从PPI网络中共获取13个关键靶基因,包含FOS、SMARCA4、SOCS3、LEP、FBXO32、MYOD1、TRIM63、SMARCA2、CALB1、MAPK12、ADIPOQ、TTN、EGR1。结论:利用生物信息学从不同角度揭示骨关节炎与正常关节滑膜间差异基因潜在特征,为骨关节炎的治疗提供新的思路。
Objective:To explore the pathogenesis of osteoarthritis by bioinformatics analysis of differential genes between osteoarthritis and normal synovium.Methods:The Gene Chip Database of Synovium was downloaded from the GEO database,and differential genes were screened by GEO2 R.An enrichment analysis was made for GO function and KEGG signaling pathway of differential genes by the DAVID 6.7 database.The PPI network was constructed by String-db database,and key target genes were obtained by Cytoscape 3.6.1 software.Results:A total of 490 differential genes,including 61 up-regulated genes and 429 down-regulated genes,were screened by GEO2 R.They mainly involved in cell differentiation,cell growth,skeletal muscle organ development,cAMP response and other physiological processes.They were mainly concentrated in extracellular matrix receptor interaction,proximal renal tubule resorption of bicarbonate,gastric acid secretion,oxytocin,cyclic adenosine phosphate/protein kinase G,adipocyte factor signaling pathway.Thirteen key target genes were obtained from the PPI network,including FOS,SMARCA4,SOCS3,LEP,FBXO32,MYOD1,TRIM63, SMARCA2,CALB1,MAPK12,ADIPOQ,TTN and EGR1.Conclusion:Bioinformatics can reveal the potential characteristics of gene differences between osteoarthritis and normal joint synovium from different perspectives,and provide new ideas for the treatment of osteoarthritis.
Objective:To explore the pathogenesis of osteoarthritis by bioinformatics analysis of differential genes between osteoarthritis and normal synovium.Methods:The Gene Chip Database of Synovium was downloaded from the GEO database,and differential genes were screened by GEO2 R.An enrichment analysis was made for GO function and KEGG signaling pathway of differential genes by the DAVID 6.7 database.The PPI network was constructed by String-db database,and key target genes were obtained by Cytoscape 3.6.1 software.Results:A total of 490 differential genes,including 61 up-regulated genes and 429 down-regulated genes,were screened by GEO2 R.They mainly involved in cell differentiation,cell growth,skeletal muscle organ development,cAMP response and other physiological processes.They were mainly concentrated in extracellular matrix receptor interaction,proximal renal tubule resorption of bicarbonate,gastric acid secretion,oxytocin,cyclic adenosine phosphate/protein kinase G,adipocyte factor signaling pathway.Thirteen key target genes were obtained from the PPI network,including FOS,SMARCA4,SOCS3,LEP,FBXO32,MYOD1,TRIM63, SMARCA2,CALB1,MAPK12,ADIPOQ,TTN and EGR1.Conclusion:Bioinformatics can reveal the potential characteristics of gene differences between osteoarthritis and normal joint synovium from different perspectives,and provide new ideas for the treatment of osteoarthritis.
引文
[1]JONSSON H.Following the genetic clues towards treatment of hand OA[J].Nat Rev Rheumatol,2018,14(Suppl1):503-504.
[2]SI HB,ZENG Y,LIU SY,et al.Intra-articular injection of microRNA-140(miRNA-140)alleviates osteoarthritis(OA)progression by modulating extracellular matrix(ECM)homeostasis in rats[J].Osteoarthritis Cartilage,2017,25(10):1698-1707.
[3]韦尼,陈自佳,李苏茜,等.蜡药疗联合美洛昔康治疗膝骨关节炎性滑膜炎36例临床观察[J].风湿病与关节炎,2018,7(1):18-22.
[4]杨威,康武林,袁普卫,等.滑膜炎在骨关节炎发病机制中作用的研究进展[J].中国康复理论与实践,2015,21(5):530-533.
[5]DE HAIR MJ,LECLERC P,NEWSUM EC,et al.Expression of Prostaglandin E2 Enzymes in the Synovium of Arthralgia Patients at Risk of Developing Rheumatoid Arthritis and in Early Arthritis Patients[J].PLoSOne,2015,10(7):e133669.
[6]BRATUS-NEUENSCHWANDER A,CASTRO-GINERF,FRANK-BERTONCELJ M,et al.Pain-Associated Transcriptome Changes in Synovium of Knee Osteoarthritis Patients[J].Genes(Basel),2018,9(7):e338.
[7]LUO H,YAO L,ZHANG Y,et al.Liquid chromatography-mass spectrometry-based quantitative proteomics analysis reveals chondroprotective effects of astragalosideⅣin interleukin-1beta-induced SW1353 chondrocyte-like cells[J].Biomed Pharmacother,2017(91):796-802.
[8]WU Y,WU T,XU B,et al.Oxytocin prevents cartilage matrix destruction via regulating matrix metalloproteinases[J].Biochem Biophys Res Commun,2017,486(3):601-606.
[9]REN YM,ZHAO X,YANG T,et al.Exploring the Key Genes and Pathways of Osteoarthritis in Knee Cartilage in a Rat Model Using Gene Expression Profiling[J].Yonsei Med J,2018,59(6):760-768.
[10]HOUARD X,GOLDRING MB,BERENBAUM F.Homeostatic mechanisms in articular cartilage and role of inflammation in osteoarthritis[J].Curr Rheumatol Rep,2013,15(11):375.
[11]ORITA S,ISHIKAWA T,MIYAGI M,et al.Percutaneously absorbed NSAIDs attenuate local production of proinflammatory cytokines and suppress the expression of c-Fos in the spinal cord of a rodent model of knee osteoarthritis[J].J Orthop Sci,2012,17(1):77-86.
[12]孙晓辉.细胞因子信号抑制因子在骨关节炎患者软骨细胞的表达[J].细胞与分子免疫学杂志,2013,29(2):186-189.
[13]KOSKINEN-KOLASA A,VUOLTEENAHO K,KOR-HONEN R,et al.Catabolic and proinflammatory effects of leptin in chondrocytes are regulated by suppressor of cytokine signaling-3[J].Arthritis Res Ther,2016,18(1):215.
[14]GUI T,HE BS,GAN Q,et al.Enhanced SOCS3 in osteoarthiritis may limit both proliferation and inflamma tion[J].Biotech Histochem,2017,92(2):107-114.
[15]陈亮,刘玉杰,魏民.瘦素对骨关节炎影响的研究进展[J].现代生物医学进展,2017,22(5):993-996.
[16]SCOTECE M,MOBASHERI A.Leptin in osteoarthritis:Focus on articular cartilage and chondrocytes[J].Life Sci,2015(140):75-78.
[17]VUOLTEENAHO K,KOSKINEN A,MOILANEN E.Leptin-a link between obesity and osteoarthritis.applications for prevention and treatment[J].Basic Clin Pharmacol Toxicol,2014,114(1):103-108.
[18]SUKARI A,MUQBIL I,MOHAMMAD RM,et al.F-BOX proteins in cancer cachexia and muscle wasting:Emerging regulators and therapeutic opportunities[J].Semin Cancer Biol,2016(36):95-104.
[19]KIM HE,RHEE J,PARK S,et al.Upregulation of Atrogin-1/FBXO32 is not necessary for cartilage destruction in mouse models of osteoarthritis[J].Osteoarthritis Cartilage,2017,25(3):397-400.
[20]LEVINGER P,CALDOW MK,BARTLETT JR,et al.The level of FoxO1 and IL-15 in skeletal muscle,serum and synovial fluid in people with knee osteoarthritis:a case control study[J].Osteoporos Int,2016,27(6):2137-2143.
[21]YADEN BC,WANG YX,WILSON JM,et al.Inhibition of activin A ameliorates skeletal muscle injury and rescues contractile properties by inducing efficient remodeling in female mice[J].Am J Pathol,2014,184(4):1152-1166.
[22]NARASIMHAN M,HONG J,ATIENO N,et al.Nrf2 deficiency promotes apoptosis and impairs PAX7/MyoDexpression in aging skeletal muscle cells[J].Free Radic Biol Med,2014(71):402-414.
[23]李俊平,徐玉明,方卫斌.低氧环境与低氧运动对骨骼肌Titin和Nebulin含量的影响[J].北京体育大学学报,2010,45(1):42-44.
[24]何莲子,邓媛媛,高健美,等.钙结合蛋白-D28K在神经退行性疾病中的作用[J].中国新药与临床杂志,2017,36(5):254-258.
[25]GAO SC,YIN HB,LIU HX,et al.Research progress on MAPK signal pathway in the pathogenesis of osteoarthritis[J].Zhongguo Gu Shang,2014,27(5):441-444.
[26]SHI J,ZHANG C,YI Z,et al.Explore the variation of MMP3,JNK,p38 MAPKs,and autophagy at the early stage of osteoarthritis[J].IUBMB Life,2016,68(4):293-302.
[27]CUI C,SHI X.miR-187 inhibits tumor growth and invasion by directly targeting MAPK12 in osteosarcoma[J].Exp Ther Med,2017,14(2):1045-1050.
[28]HAMALAINEN S,SOLOVIEVA S,VEHMAS T,et al.Adipokine genes and radiographic hand osteoarthritis in Finnish women:a cross-sectional study[J].Scand JRheumatol,2018,47(1):71-78.
[29]NEBBAKI SS,EL MF,AFIF H,et al.Egr-1 contributes to IL-1-mediated down-regulation of peroxisome proliferator-activated receptor gamma expression in human osteoarthritic chondrocytes[J].Arthritis Res Ther,2012,14(2):R69.
[30]AYDIN?Z,VERMEULEN W,LANS H.ISWI chromatin remodeling complexes in the DNA damage response[J].Cell Cycle,2014,13(19):3016-3025.
[2]SI HB,ZENG Y,LIU SY,et al.Intra-articular injection of microRNA-140(miRNA-140)alleviates osteoarthritis(OA)progression by modulating extracellular matrix(ECM)homeostasis in rats[J].Osteoarthritis Cartilage,2017,25(10):1698-1707.
[3]韦尼,陈自佳,李苏茜,等.蜡药疗联合美洛昔康治疗膝骨关节炎性滑膜炎36例临床观察[J].风湿病与关节炎,2018,7(1):18-22.
[4]杨威,康武林,袁普卫,等.滑膜炎在骨关节炎发病机制中作用的研究进展[J].中国康复理论与实践,2015,21(5):530-533.
[5]DE HAIR MJ,LECLERC P,NEWSUM EC,et al.Expression of Prostaglandin E2 Enzymes in the Synovium of Arthralgia Patients at Risk of Developing Rheumatoid Arthritis and in Early Arthritis Patients[J].PLoSOne,2015,10(7):e133669.
[6]BRATUS-NEUENSCHWANDER A,CASTRO-GINERF,FRANK-BERTONCELJ M,et al.Pain-Associated Transcriptome Changes in Synovium of Knee Osteoarthritis Patients[J].Genes(Basel),2018,9(7):e338.
[7]LUO H,YAO L,ZHANG Y,et al.Liquid chromatography-mass spectrometry-based quantitative proteomics analysis reveals chondroprotective effects of astragalosideⅣin interleukin-1beta-induced SW1353 chondrocyte-like cells[J].Biomed Pharmacother,2017(91):796-802.
[8]WU Y,WU T,XU B,et al.Oxytocin prevents cartilage matrix destruction via regulating matrix metalloproteinases[J].Biochem Biophys Res Commun,2017,486(3):601-606.
[9]REN YM,ZHAO X,YANG T,et al.Exploring the Key Genes and Pathways of Osteoarthritis in Knee Cartilage in a Rat Model Using Gene Expression Profiling[J].Yonsei Med J,2018,59(6):760-768.
[10]HOUARD X,GOLDRING MB,BERENBAUM F.Homeostatic mechanisms in articular cartilage and role of inflammation in osteoarthritis[J].Curr Rheumatol Rep,2013,15(11):375.
[11]ORITA S,ISHIKAWA T,MIYAGI M,et al.Percutaneously absorbed NSAIDs attenuate local production of proinflammatory cytokines and suppress the expression of c-Fos in the spinal cord of a rodent model of knee osteoarthritis[J].J Orthop Sci,2012,17(1):77-86.
[12]孙晓辉.细胞因子信号抑制因子在骨关节炎患者软骨细胞的表达[J].细胞与分子免疫学杂志,2013,29(2):186-189.
[13]KOSKINEN-KOLASA A,VUOLTEENAHO K,KOR-HONEN R,et al.Catabolic and proinflammatory effects of leptin in chondrocytes are regulated by suppressor of cytokine signaling-3[J].Arthritis Res Ther,2016,18(1):215.
[14]GUI T,HE BS,GAN Q,et al.Enhanced SOCS3 in osteoarthiritis may limit both proliferation and inflamma tion[J].Biotech Histochem,2017,92(2):107-114.
[15]陈亮,刘玉杰,魏民.瘦素对骨关节炎影响的研究进展[J].现代生物医学进展,2017,22(5):993-996.
[16]SCOTECE M,MOBASHERI A.Leptin in osteoarthritis:Focus on articular cartilage and chondrocytes[J].Life Sci,2015(140):75-78.
[17]VUOLTEENAHO K,KOSKINEN A,MOILANEN E.Leptin-a link between obesity and osteoarthritis.applications for prevention and treatment[J].Basic Clin Pharmacol Toxicol,2014,114(1):103-108.
[18]SUKARI A,MUQBIL I,MOHAMMAD RM,et al.F-BOX proteins in cancer cachexia and muscle wasting:Emerging regulators and therapeutic opportunities[J].Semin Cancer Biol,2016(36):95-104.
[19]KIM HE,RHEE J,PARK S,et al.Upregulation of Atrogin-1/FBXO32 is not necessary for cartilage destruction in mouse models of osteoarthritis[J].Osteoarthritis Cartilage,2017,25(3):397-400.
[20]LEVINGER P,CALDOW MK,BARTLETT JR,et al.The level of FoxO1 and IL-15 in skeletal muscle,serum and synovial fluid in people with knee osteoarthritis:a case control study[J].Osteoporos Int,2016,27(6):2137-2143.
[21]YADEN BC,WANG YX,WILSON JM,et al.Inhibition of activin A ameliorates skeletal muscle injury and rescues contractile properties by inducing efficient remodeling in female mice[J].Am J Pathol,2014,184(4):1152-1166.
[22]NARASIMHAN M,HONG J,ATIENO N,et al.Nrf2 deficiency promotes apoptosis and impairs PAX7/MyoDexpression in aging skeletal muscle cells[J].Free Radic Biol Med,2014(71):402-414.
[23]李俊平,徐玉明,方卫斌.低氧环境与低氧运动对骨骼肌Titin和Nebulin含量的影响[J].北京体育大学学报,2010,45(1):42-44.
[24]何莲子,邓媛媛,高健美,等.钙结合蛋白-D28K在神经退行性疾病中的作用[J].中国新药与临床杂志,2017,36(5):254-258.
[25]GAO SC,YIN HB,LIU HX,et al.Research progress on MAPK signal pathway in the pathogenesis of osteoarthritis[J].Zhongguo Gu Shang,2014,27(5):441-444.
[26]SHI J,ZHANG C,YI Z,et al.Explore the variation of MMP3,JNK,p38 MAPKs,and autophagy at the early stage of osteoarthritis[J].IUBMB Life,2016,68(4):293-302.
[27]CUI C,SHI X.miR-187 inhibits tumor growth and invasion by directly targeting MAPK12 in osteosarcoma[J].Exp Ther Med,2017,14(2):1045-1050.
[28]HAMALAINEN S,SOLOVIEVA S,VEHMAS T,et al.Adipokine genes and radiographic hand osteoarthritis in Finnish women:a cross-sectional study[J].Scand JRheumatol,2018,47(1):71-78.
[29]NEBBAKI SS,EL MF,AFIF H,et al.Egr-1 contributes to IL-1-mediated down-regulation of peroxisome proliferator-activated receptor gamma expression in human osteoarthritic chondrocytes[J].Arthritis Res Ther,2012,14(2):R69.
[30]AYDIN?Z,VERMEULEN W,LANS H.ISWI chromatin remodeling complexes in the DNA damage response[J].Cell Cycle,2014,13(19):3016-3025.