Study on gene expression patterns and functional pathways of peripheral blood monocytes reveals potential molecular mechanism of surgical treatment for periodontitis
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摘要
BACKGROUND Periodontitis is a chronic inflammation of periodontal supporting tissue caused by local factors. Periodontal surgery can change the gene expression of peripheral blood mononuclear cells. However, little is known about the potential mechanism of surgical treatment for periodontitis.AIM To explore the potential molecular mechanism of surgical treatment for periodontitis.METHODS First, based on the expression profiles of genes related to surgical treatment for periodontitis, a set of expression disorder modules related to surgical treatment for periodontitis were obtained by enrichment analysis. Subsequently, based on crosstalk analysis, we proved that there was a significant crosstalk relationship between module 3 and module 5. Finally, based on predictive analysis of multidimensional regulators, we identified a series of regulatory factors, such as endogenous genes, non-coding RNAs(ncRNAs), and transcription factors, which have potential regulatory effects on periodontitis.RESULTS A total of 337 genes related to surgical treatment for periodontitis were obtained,and 3896 genes related to periodontitis were amplified. Eight expression modulesof periodontitis were obtained, involving the aggregation of 2672 gene modules.These modules are mainly involved in G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger, and adenylate cyclasemodulating G-protein coupled receptor signaling pathway. In addition, eight endogenous genes(including EGF, RPS27 A, and GNB3) were screened by network connectivity analysis. Finally, based on this set of potential dysfunction modules, 94 transcription factors(including NFKB1, SP1, and STAT3) and 1198 ncRNAs(including MALAT1, CRNDE, and ANCR) were revealed. These core regulators are thought to be involved in the potential molecular mechanism of periodontitis after surgical treatment.CONCLUSION Based on the results of this study, we can show biologists and pharmacists a new idea to reveal the potential molecular mechanism of surgical treatment for periodontitis, and provide valuable reference for follow-up treatment programs.
BACKGROUND Periodontitis is a chronic inflammation of periodontal supporting tissue caused by local factors. Periodontal surgery can change the gene expression of peripheral blood mononuclear cells. However, little is known about the potential mechanism of surgical treatment for periodontitis.AIM To explore the potential molecular mechanism of surgical treatment for periodontitis.METHODS First, based on the expression profiles of genes related to surgical treatment for periodontitis, a set of expression disorder modules related to surgical treatment for periodontitis were obtained by enrichment analysis. Subsequently, based on crosstalk analysis, we proved that there was a significant crosstalk relationship between module 3 and module 5. Finally, based on predictive analysis of multidimensional regulators, we identified a series of regulatory factors, such as endogenous genes, non-coding RNAs(ncRNAs), and transcription factors, which have potential regulatory effects on periodontitis.RESULTS A total of 337 genes related to surgical treatment for periodontitis were obtained,and 3896 genes related to periodontitis were amplified. Eight expression modulesof periodontitis were obtained, involving the aggregation of 2672 gene modules.These modules are mainly involved in G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger, and adenylate cyclasemodulating G-protein coupled receptor signaling pathway. In addition, eight endogenous genes(including EGF, RPS27 A, and GNB3) were screened by network connectivity analysis. Finally, based on this set of potential dysfunction modules, 94 transcription factors(including NFKB1, SP1, and STAT3) and 1198 ncRNAs(including MALAT1, CRNDE, and ANCR) were revealed. These core regulators are thought to be involved in the potential molecular mechanism of periodontitis after surgical treatment.CONCLUSION Based on the results of this study, we can show biologists and pharmacists a new idea to reveal the potential molecular mechanism of surgical treatment for periodontitis, and provide valuable reference for follow-up treatment programs.
BACKGROUND Periodontitis is a chronic inflammation of periodontal supporting tissue caused by local factors. Periodontal surgery can change the gene expression of peripheral blood mononuclear cells. However, little is known about the potential mechanism of surgical treatment for periodontitis.AIM To explore the potential molecular mechanism of surgical treatment for periodontitis.METHODS First, based on the expression profiles of genes related to surgical treatment for periodontitis, a set of expression disorder modules related to surgical treatment for periodontitis were obtained by enrichment analysis. Subsequently, based on crosstalk analysis, we proved that there was a significant crosstalk relationship between module 3 and module 5. Finally, based on predictive analysis of multidimensional regulators, we identified a series of regulatory factors, such as endogenous genes, non-coding RNAs(ncRNAs), and transcription factors, which have potential regulatory effects on periodontitis.RESULTS A total of 337 genes related to surgical treatment for periodontitis were obtained,and 3896 genes related to periodontitis were amplified. Eight expression modulesof periodontitis were obtained, involving the aggregation of 2672 gene modules.These modules are mainly involved in G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger, and adenylate cyclasemodulating G-protein coupled receptor signaling pathway. In addition, eight endogenous genes(including EGF, RPS27 A, and GNB3) were screened by network connectivity analysis. Finally, based on this set of potential dysfunction modules, 94 transcription factors(including NFKB1, SP1, and STAT3) and 1198 ncRNAs(including MALAT1, CRNDE, and ANCR) were revealed. These core regulators are thought to be involved in the potential molecular mechanism of periodontitis after surgical treatment.CONCLUSION Based on the results of this study, we can show biologists and pharmacists a new idea to reveal the potential molecular mechanism of surgical treatment for periodontitis, and provide valuable reference for follow-up treatment programs.
引文
1 Larsson L,Thorbert-Mros S,Rymo L,Berglundh T.Interleukin-10 genotypes of the-1087 single nucleotide polymorphism influence sp1 expression in periodontitis lesions.J Periodontol 2011;82:1376-1382[PMID:21309719 DOI:10.1902/jop.2011.100623]
2 Peng W,Deng W,Zhang J,Pei G,Rong Q,Zhu S.Long noncoding RNA ANCR suppresses bone formation of periodontal ligament stem cells via sponging miRNA-758.Biochem Biophys Res Commun2018;503:815-821[PMID:29913147 DOI:10.1016/j.bbrc.2018.06.081]
3 Schenkein HA,Sabatini R,Koertge TE,Brooks CN,Purkall DB.Anti-cardiolipin from periodontitis patients induces MCP-1 production by human umbilical vein endothelial cells.J Clin Periodontol 2013;40:212-217[PMID:23281818 DOI:10.1111/jcpe.12043]
4 Behle JH,Papapanou PN.Periodontal infections and atherosclerotic vascular disease:an update.Int Dent J 2006;56:256-262[PMID:16972401 DOI:10.1111/j.1875-595X.2006.tb00110.x]
5 van Winkelhoff AJ,Winkel EG,Vandenbroucke-Grauls CM.[Periodontitis:a hidden chronic infection].Ned Tijdschr Geneeskd 2001;145:557-563[PMID:11293993]
6 Schaefer AS,Richter GM,Nothnagel M,Laine ML,Rühling A,Sch?fer C,Cordes N,Noack B,Folwaczny M,Glas J,D?rfer C,Dommisch H,Groessner-Schreiber B,Jepsen S,Loos BG,Schreiber S.A3'UTR transition within DEFB1 is associated with chronic and aggressive periodontitis.Genes Immun2010;11:45-54[PMID:19829306 DOI:10.1038/gene.2009.75]
7 Horning GM,Hatch CL,Lutskus J.The prevalence of periodontitis in a military treatment population.JAm Dent Assoc 1990;121:616-622[PMID:2229742 DOI:10.14219/jada.archive.1990.0221]
8 Preshaw PM,Alba AL,Herrera D,Jepsen S,Konstantinidis A,Makrilakis K,Taylor R.Periodontitis and diabetes:a two-way relationship.Diabetologia 2012;55:21-31[PMID:22057194 DOI:10.1007/s00125-011-2342-y]
9 Kumar RS,Prakash S.Impaired neutrophil and monocyte chemotaxis in chronic and aggressive periodontitis and effects of periodontal therapy.Indian J Dent Res 2012;23:69-74[PMID:22842253DOI:10.4103/0970-9290.99042]
10 Novak MJ,Novak KF.Early-onset periodontitis.Curr Opin Periodontol 1996;3:45-58[PMID:8624569]
11 Kranthi J,Sudhakar K,Kulshrestha R,Raju PK,Razdan A,Srinivasa Ts.Comparison of the serum immunoglobulin IgM level in diabetic and nondiabetic patients with chronic periodontitis.J Contemp Dent Pract 2013;14:814-818[PMID:24685780 DOI:10.5005/jp-journals-10024-1408]
12 Kinoshita N,Awano S,Yoshida A,Soh I,Ansai T.Periodontal disease and gene-expression levels of metalloendopeptidases in human buccal mucosal epithelium.J Periodontal Res 2013;48:606-614[PMID:23360525 DOI:10.1111/jre.12045]
13 Iacopino AM,Cutler CW.Pathophysiological relationships between periodontitis and systemic disease:recent concepts involving serum lipids.J Periodontol 2000;71:1375-1384[PMID:10972656 DOI:10.1902/jop.2000.71.8.1375]
14 van Winkelhoff AJ,Tijhof CJ,de Graaff J.Microbiological and clinical results of metronidazole plus amoxicillin therapy in Actinobacillus actinomycetemcomitans-associated periodontitis.J Periodontol1992;63:52-57[PMID:1313103 DOI:10.1902/jop.1992.63.1.52]
15 Seymour GJ,Palmer JE,Leishman SJ,Do HL,Westerman B,Carle AD,Faddy MJ,West MJ,Cullinan MP.Influence of a triclosan toothpaste on periodontopathic bacteria and periodontitis progression in cardiovascular patients:a randomized controlled trial.J Periodontal Res 2017;52:61-73[PMID:26932733 DOI:10.1111/jre.12369]
16 Tucker R.Periodontitis and pregnancy.J R Soc Promot Health 2006;126:24-27[PMID:16478012 DOI:10.1177/1466424006061170]
17 D'Aiuto F,Nibali L,Parkar M,Patel K,Suvan J,Donos N.Oxidative stress,systemic inflammation,and severe periodontitis.J Dent Res 2010;89:1241-1246[PMID:20739696 DOI:10.1177/0022034510375830]
18 Kido J,Bando Y,Bando M,Kajiura Y,Hiroshima Y,Inagaki Y,Murata H,Ikuta T,Kido R,Naruishi K,Funaki M,Nagata T.YKL-40 level in gingival crevicular fluid from patients with periodontitis and type 2diabetes.Oral Dis 2015;21:667-673[PMID:25740558 DOI:10.1111/odi.12334]
19 Bostanci N,Oztürk V?,Emingil G,Belibasakis GN.Elevated oral and systemic levels of soluble triggering receptor expressed on myeloid cells-1(sTREM-1)in periodontitis.J Dent Res 2013;92:161-165[PMID:23242230 DOI:10.1177/0022034512470691]
20 Pejcic A,Kesic LJ,Milasin J.C-reactive protein as a systemic marker of inflammation in periodontitis.Eur J Clin Microbiol Infect Dis 2011;30:407-414[PMID:21057970 DOI:10.1007/s10096-010-1101-1]
21 Papapanou PN,Sedaghatfar MH,Demmer RT,Wolf DL,Yang J,Roth GA,Celenti R,Belusko PB,Lalla E,Pavlidis P.Periodontal therapy alters gene expression of peripheral blood monocytes.J Clin Periodontol 2007;34:736-747[PMID:17716309 DOI:10.1111/j.1600-051X.2007.01113.x]
22 Langfelder P,Horvath S.WGCNA:an R package for weighted correlation network analysis.BMCBioinformatics 2008;9:559[PMID:19114008 DOI:10.1186/1471-2105-9-559]
23 Hopf TA,Green AG,Schubert B,Mersmann S,Sch?rfe CPI,Ingraham JB,Toth-Petroczy A,Brock K,Riesselman AJ,Palmedo P,Kang C,Sheridan R,Draizen EJ,Dallago C,Sander C,Marks DS.The EVcouplings Python framework for coevolutionary sequence analysis.Bioinformatics 2018[PMID:30304492 DOI:10.1093/bioinformatics/bty862]
24 Carlin DE,Demchak B,Pratt D,Sage E,Ideker T.Network propagation in the cytoscape cyberinfrastructure.PLoS Comput Biol 2017;13:e1005598[PMID:29023449 DOI:10.1371/journal.pcbi.1005598]
25 Yu G,Wang LG,Han Y,He QY.clusterProfiler:an R package for comparing biological themes among gene clusters.OMICS 2012;16:284-287[PMID:22455463 DOI:10.1089/omi.2011.0118]
26 Han H,Cho JW,Lee S,Yun A,Kim H,Bae D,Yang S,Kim CY,Lee M,Kim E,Lee S,Kang B,Jeong D,Kim Y,Jeon HN,Jung H,Nam S,Chung M,Kim JH,Lee I.TRRUST v2:an expanded reference database of human and mouse transcriptional regulatory interactions.Nucleic Acids Res 2018;46:D380-D386[PMID:29087512 DOI:10.1093/nar/gkx1013]
27 Yi Y,Zhao Y,Li C,Zhang L,Huang H,Li Y,Liu L,Hou P,Cui T,Tan P,Hu Y,Zhang T,Huang Y,Li X,Yu J,Wang D.RAID v2.0:an updated resource of RNA-associated interactions across organisms.Nucleic Acids Res 2017;45:D115-D118[PMID:27899615 DOI:10.1093/nar/gkw1052]
28 Grigoriadou ME,Koutayas SO,Madianos PN,Strub JR.Interleukin-1 as a genetic marker for periodontitis:review of the literature.Quintessence Int 2010;41:517-525[PMID:20490394]
29 Petrovich IuA,Podorozhnaia RP,Genesina TI,Beloklitskaia GF.[Adenylate cyclase and guanylate cyclase in the saliva of healthy persons and in periodontitis].Stomatologiia(Mosk)1991;30-33[PMID:1685812]
30 Beklen A,Al-Samadi A,Konttinen YT.Expression of cathepsin K in periodontitis and in gingival fibroblasts.Oral Dis 2015;21:163-169[PMID:24661326 DOI:10.1111/odi.12230]
31 Jimi E,Fukushima H.[NF-κB signaling pathways and the future perspectives of bone disease therapy using selective inhibitors of NF-κB].Clin Calcium 2016;26:298-304[PMID:26813510]
32 Wang Q,Li H,Xie H,Fu M,Guo B,Ding Y,Li W,Yu H.25-Hydroxyvitamin D3 attenuates experimental periodontitis through downregulation of TLR4 and JAK1/STAT3 signaling in diabetic mice.J Steroid Biochem Mol Biol 2013;135:43-50[PMID:23333931 DOI:10.1016/j.jsbmb.2013.01.008]
33 Li S,Liu X,Li H,Pan H,Acharya A,Deng Y,Yu Y,Haak R,Schmidt J,Schmalz G,Ziebolz D.Integrated analysis of long noncoding RNA-associated competing endogenous RNA network in periodontitis.J Periodontal Res 2018;53:495-505[PMID:29516510 DOI:10.1111/jre.12539]
34 Vaahtokari A,Aberg T,Thesleff I.Apoptosis in the developing tooth:association with an embryonic signaling center and suppression by EGF and FGF-4.Development 1996;122:121-129[PMID:8565823]
35 Alves JB,Ferreira CL,Martins AF,Silva GA,Alves GD,Paulino TP,Ciancaglini P,Thedei G,Napimoga MH.Local delivery of EGF-liposome mediated bone modeling in orthodontic tooth movement by increasing RANKL expression.Life Sci 2009;85:693-699[PMID:19796647 DOI:10.1016/j.lfs.2009.09.010]
2 Peng W,Deng W,Zhang J,Pei G,Rong Q,Zhu S.Long noncoding RNA ANCR suppresses bone formation of periodontal ligament stem cells via sponging miRNA-758.Biochem Biophys Res Commun2018;503:815-821[PMID:29913147 DOI:10.1016/j.bbrc.2018.06.081]
3 Schenkein HA,Sabatini R,Koertge TE,Brooks CN,Purkall DB.Anti-cardiolipin from periodontitis patients induces MCP-1 production by human umbilical vein endothelial cells.J Clin Periodontol 2013;40:212-217[PMID:23281818 DOI:10.1111/jcpe.12043]
4 Behle JH,Papapanou PN.Periodontal infections and atherosclerotic vascular disease:an update.Int Dent J 2006;56:256-262[PMID:16972401 DOI:10.1111/j.1875-595X.2006.tb00110.x]
5 van Winkelhoff AJ,Winkel EG,Vandenbroucke-Grauls CM.[Periodontitis:a hidden chronic infection].Ned Tijdschr Geneeskd 2001;145:557-563[PMID:11293993]
6 Schaefer AS,Richter GM,Nothnagel M,Laine ML,Rühling A,Sch?fer C,Cordes N,Noack B,Folwaczny M,Glas J,D?rfer C,Dommisch H,Groessner-Schreiber B,Jepsen S,Loos BG,Schreiber S.A3'UTR transition within DEFB1 is associated with chronic and aggressive periodontitis.Genes Immun2010;11:45-54[PMID:19829306 DOI:10.1038/gene.2009.75]
7 Horning GM,Hatch CL,Lutskus J.The prevalence of periodontitis in a military treatment population.JAm Dent Assoc 1990;121:616-622[PMID:2229742 DOI:10.14219/jada.archive.1990.0221]
8 Preshaw PM,Alba AL,Herrera D,Jepsen S,Konstantinidis A,Makrilakis K,Taylor R.Periodontitis and diabetes:a two-way relationship.Diabetologia 2012;55:21-31[PMID:22057194 DOI:10.1007/s00125-011-2342-y]
9 Kumar RS,Prakash S.Impaired neutrophil and monocyte chemotaxis in chronic and aggressive periodontitis and effects of periodontal therapy.Indian J Dent Res 2012;23:69-74[PMID:22842253DOI:10.4103/0970-9290.99042]
10 Novak MJ,Novak KF.Early-onset periodontitis.Curr Opin Periodontol 1996;3:45-58[PMID:8624569]
11 Kranthi J,Sudhakar K,Kulshrestha R,Raju PK,Razdan A,Srinivasa Ts.Comparison of the serum immunoglobulin IgM level in diabetic and nondiabetic patients with chronic periodontitis.J Contemp Dent Pract 2013;14:814-818[PMID:24685780 DOI:10.5005/jp-journals-10024-1408]
12 Kinoshita N,Awano S,Yoshida A,Soh I,Ansai T.Periodontal disease and gene-expression levels of metalloendopeptidases in human buccal mucosal epithelium.J Periodontal Res 2013;48:606-614[PMID:23360525 DOI:10.1111/jre.12045]
13 Iacopino AM,Cutler CW.Pathophysiological relationships between periodontitis and systemic disease:recent concepts involving serum lipids.J Periodontol 2000;71:1375-1384[PMID:10972656 DOI:10.1902/jop.2000.71.8.1375]
14 van Winkelhoff AJ,Tijhof CJ,de Graaff J.Microbiological and clinical results of metronidazole plus amoxicillin therapy in Actinobacillus actinomycetemcomitans-associated periodontitis.J Periodontol1992;63:52-57[PMID:1313103 DOI:10.1902/jop.1992.63.1.52]
15 Seymour GJ,Palmer JE,Leishman SJ,Do HL,Westerman B,Carle AD,Faddy MJ,West MJ,Cullinan MP.Influence of a triclosan toothpaste on periodontopathic bacteria and periodontitis progression in cardiovascular patients:a randomized controlled trial.J Periodontal Res 2017;52:61-73[PMID:26932733 DOI:10.1111/jre.12369]
16 Tucker R.Periodontitis and pregnancy.J R Soc Promot Health 2006;126:24-27[PMID:16478012 DOI:10.1177/1466424006061170]
17 D'Aiuto F,Nibali L,Parkar M,Patel K,Suvan J,Donos N.Oxidative stress,systemic inflammation,and severe periodontitis.J Dent Res 2010;89:1241-1246[PMID:20739696 DOI:10.1177/0022034510375830]
18 Kido J,Bando Y,Bando M,Kajiura Y,Hiroshima Y,Inagaki Y,Murata H,Ikuta T,Kido R,Naruishi K,Funaki M,Nagata T.YKL-40 level in gingival crevicular fluid from patients with periodontitis and type 2diabetes.Oral Dis 2015;21:667-673[PMID:25740558 DOI:10.1111/odi.12334]
19 Bostanci N,Oztürk V?,Emingil G,Belibasakis GN.Elevated oral and systemic levels of soluble triggering receptor expressed on myeloid cells-1(sTREM-1)in periodontitis.J Dent Res 2013;92:161-165[PMID:23242230 DOI:10.1177/0022034512470691]
20 Pejcic A,Kesic LJ,Milasin J.C-reactive protein as a systemic marker of inflammation in periodontitis.Eur J Clin Microbiol Infect Dis 2011;30:407-414[PMID:21057970 DOI:10.1007/s10096-010-1101-1]
21 Papapanou PN,Sedaghatfar MH,Demmer RT,Wolf DL,Yang J,Roth GA,Celenti R,Belusko PB,Lalla E,Pavlidis P.Periodontal therapy alters gene expression of peripheral blood monocytes.J Clin Periodontol 2007;34:736-747[PMID:17716309 DOI:10.1111/j.1600-051X.2007.01113.x]
22 Langfelder P,Horvath S.WGCNA:an R package for weighted correlation network analysis.BMCBioinformatics 2008;9:559[PMID:19114008 DOI:10.1186/1471-2105-9-559]
23 Hopf TA,Green AG,Schubert B,Mersmann S,Sch?rfe CPI,Ingraham JB,Toth-Petroczy A,Brock K,Riesselman AJ,Palmedo P,Kang C,Sheridan R,Draizen EJ,Dallago C,Sander C,Marks DS.The EVcouplings Python framework for coevolutionary sequence analysis.Bioinformatics 2018[PMID:30304492 DOI:10.1093/bioinformatics/bty862]
24 Carlin DE,Demchak B,Pratt D,Sage E,Ideker T.Network propagation in the cytoscape cyberinfrastructure.PLoS Comput Biol 2017;13:e1005598[PMID:29023449 DOI:10.1371/journal.pcbi.1005598]
25 Yu G,Wang LG,Han Y,He QY.clusterProfiler:an R package for comparing biological themes among gene clusters.OMICS 2012;16:284-287[PMID:22455463 DOI:10.1089/omi.2011.0118]
26 Han H,Cho JW,Lee S,Yun A,Kim H,Bae D,Yang S,Kim CY,Lee M,Kim E,Lee S,Kang B,Jeong D,Kim Y,Jeon HN,Jung H,Nam S,Chung M,Kim JH,Lee I.TRRUST v2:an expanded reference database of human and mouse transcriptional regulatory interactions.Nucleic Acids Res 2018;46:D380-D386[PMID:29087512 DOI:10.1093/nar/gkx1013]
27 Yi Y,Zhao Y,Li C,Zhang L,Huang H,Li Y,Liu L,Hou P,Cui T,Tan P,Hu Y,Zhang T,Huang Y,Li X,Yu J,Wang D.RAID v2.0:an updated resource of RNA-associated interactions across organisms.Nucleic Acids Res 2017;45:D115-D118[PMID:27899615 DOI:10.1093/nar/gkw1052]
28 Grigoriadou ME,Koutayas SO,Madianos PN,Strub JR.Interleukin-1 as a genetic marker for periodontitis:review of the literature.Quintessence Int 2010;41:517-525[PMID:20490394]
29 Petrovich IuA,Podorozhnaia RP,Genesina TI,Beloklitskaia GF.[Adenylate cyclase and guanylate cyclase in the saliva of healthy persons and in periodontitis].Stomatologiia(Mosk)1991;30-33[PMID:1685812]
30 Beklen A,Al-Samadi A,Konttinen YT.Expression of cathepsin K in periodontitis and in gingival fibroblasts.Oral Dis 2015;21:163-169[PMID:24661326 DOI:10.1111/odi.12230]
31 Jimi E,Fukushima H.[NF-κB signaling pathways and the future perspectives of bone disease therapy using selective inhibitors of NF-κB].Clin Calcium 2016;26:298-304[PMID:26813510]
32 Wang Q,Li H,Xie H,Fu M,Guo B,Ding Y,Li W,Yu H.25-Hydroxyvitamin D3 attenuates experimental periodontitis through downregulation of TLR4 and JAK1/STAT3 signaling in diabetic mice.J Steroid Biochem Mol Biol 2013;135:43-50[PMID:23333931 DOI:10.1016/j.jsbmb.2013.01.008]
33 Li S,Liu X,Li H,Pan H,Acharya A,Deng Y,Yu Y,Haak R,Schmidt J,Schmalz G,Ziebolz D.Integrated analysis of long noncoding RNA-associated competing endogenous RNA network in periodontitis.J Periodontal Res 2018;53:495-505[PMID:29516510 DOI:10.1111/jre.12539]
34 Vaahtokari A,Aberg T,Thesleff I.Apoptosis in the developing tooth:association with an embryonic signaling center and suppression by EGF and FGF-4.Development 1996;122:121-129[PMID:8565823]
35 Alves JB,Ferreira CL,Martins AF,Silva GA,Alves GD,Paulino TP,Ciancaglini P,Thedei G,Napimoga MH.Local delivery of EGF-liposome mediated bone modeling in orthodontic tooth movement by increasing RANKL expression.Life Sci 2009;85:693-699[PMID:19796647 DOI:10.1016/j.lfs.2009.09.010]