Micro RNAs In Periodontal Disease – A Review


  • Mekha Grace Varghese Department of Periodontics, Pushpagiri College of Dental Sciences, Kerala
  • Thomas George Valliaveettil Department of Periodontics, Pushpagiri College of Dental Sciences, Kerala
  • Annie Kitty George Department of Periodontics, Pushpagiri College of Dental Sciences, Kerala
  • Saranya Rajan Department of Periodontics, Pushpagiri College of Dental Sciences, Kerala




microRNA, biogenesis, profiling, innate immunity, acquired immunity, bone remodelling


microRNAs (miRNAs) constitute a family of small, non-coding RNA molecules that regulate gene expression and protein expression. microRNAs have influence on a broad range of physiologic and pathologic conditions. They are also considered as promising biomarkers especially when they are secreted extracellularly. In the inflammatory pathways, they dysregulate the molecular processes and contribute to the development of chronic inflammatory diseases including periodontitis. In this review, we provide an overview of miRNA characteristics, biogenesis, mechanisms of action and profiling methods. In addition, the role of miRNAs in the pathobiology of periodontitis, especially those pertaining to the cellular and molecular pathways of inflammation has been considered to enhance our understanding of the pathobiology of periodontitis.


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1. Crick FH. The biological replication of macromolecules. Symp. Soc. Exp. Biol. 1958;138–163.
2. Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009;19:92–105.
3. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene LIN-4 encodes small RNAs with antisense complementarity to LIN-14. Cell. 1993;75:843–854.
4. Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of the heterochronic gene LIN-14 by LIN-4 mediates temporal pattern formation in C. elegans. Cell. 1993;75:855–862.
5. Griffiths-Jones S. The microRNA registry. Nucleic Acids Res. 2004;32:D109–D111.
6. Ha M, Kim VN. Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol. 2014;15:509–524.
7. Marco A, Ninova M, Griffiths-Jones S. Multiple products from microRNA transcripts. Biochem Soc Trans. 2013;41:850–854.
8. Borchert GM, Lanier W, Davidson BL. RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol. 2006;13:1097–1101.
9. Roth BM, Ishimaru D, Hennig M. The core microprocessor component diGeorge syndrome critical region 8 (DGCR8) is a nonspecific RNA-binding protein. J Biol Chem. 2013;288:26785–26799.
10. Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Radmark O, Kim S, Kim VN. The nuclear RNAse III Drosha initiates microRNA processing. Nature. 2003;425:415–419.
11. Yi R, Qin Y, Macara IG, Cullen BR. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev. 2003;17:3011–3016.
12. Guo L, Zhao Y, Yang S, Zhang H, Chen F. A genome-wide screen for non-template nucleotides and isomir repertoires in miRNAs indicates dynamic and versatile microRNAome. Mol Biol Rep. 2014;41:6649–6658.
13. Guo L, Chen F. A challenge for miRNA: Multiple isomirs in miRNAomics. Gene. 2014;544:1–7.
14. Neilsen CT, Goodall GJ, Bracken CP. IsomiRs--the overlooked repertoire in the dynamic microRNAome. Trends Genet. 2012;28:544–549.
15. Tan GC, Chan E, Molnar A, Sarkar R, Alexieva D, Isa IM, Robinson S, Zhang S, Ellis P, Langford CF, Guillot PV, Chandrashekran A, Fisk NM, Castellano L, Meister G, Winston RM, Cui W, Baulcombe D, Dibb NJ. 5' isomir variation is of functional and evolutionary importance. Nucleic Acids Res. 2014;42:9424–9435.
16. Martin HC, Wani S, Steptoe AL, Krishnan K, Nones K, Nourbakhsh E, Vlassov A, Grimmond SM, Cloonan N. Imperfect centered miRNA binding sites are common and can mediate repression of target mRNAs. Genome Biol. 2014;15:R51.
17. Huntzinger E, Izaurralde E. Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet. 2011;12:99–110.
18. Ipsaro JJ, Joshua-Tor L. From guide to target: molecular insights into eukaryotic RNA-interference machinery. Nat Struct Mol Biol. 2015;22:20–28.
19. Forman JJ, Legesse-Miller A, Coller HA. A search for conserved sequences in coding regions reveals that the let-7 microRNA targets Dicer within its coding sequence. Proc Natl Acad Sci USA. 2008;105:14879–84.
20. Zhang J, ZhouW, Liu Y, Liu T, Li C,Wang L. Oncogenic role of microRNA-532-5p in human colorectal cancer via targeting of the 5′ UTR of RUNX3. Oncol Lett. 2018;15:7215–7220.
21. Dharap A, Pokrzywa C, Murali S, Pandi G, Vemuganti R. MicroRNA miR- 324-3p induces promoter-mediated expression of RelA gene. PLoS ONE 2013;8:e79467.
22. Meister G. Argonaute proteins: Functional insights and emerging roles. Nat Rev Genet. 2013;14:447–459.
23. Jonas S, Izaurralde E. Towards a molecular understanding of microRNA-mediated gene silencing. Nat Rev Genet. 2015;16:421–33.
24. Jo MH, Shin S, Jung SR, Kim E, Song JJ, Hohng S. Human Argonaute 2 Has diverse reaction pathways on Target RNAs. Mol Cell. 2015;59:117–24.
25. Murata K, Yoshitomi H, Furu M, Ishikawa M, Shibuya H, Ito H, Matsuda Micro RNA-451 down-regulates neutrophil chemotaxis via p38 MAPK. Arthritis Rheumatol. 2014;66:549–559.
26. Nahid MA, Rivera M, Lucas A, Chan EK, Kesavalu L. Polymicrobial infection with periodontal pathogens specifically enhances microRNA miR-146a in APOE−/− mice during experimental periodontal disease. Infect Immun. 2011;79:1597–1605.
27. Nakao A, Kajiya H, Fukushima H, Fukushima A, Anan H, Ozeki S, Okabe K. PTHRP induces notch signaling in periodontal ligament cells. J Dent Res. 2009;88:551–556.
28. Nallamshetty S, Chan SY, Loscalzo J. Hypoxia: A master regulator of microRNA biogenesis and activity. Free Radic Biol Med. 2013;64:20–30.
29. Accerbi M, et al. Methods for isolation of total RNA to recover miRNAs and other small RNAs from diverse species. Methods Mol Biol. 2010;592:31–50.
30. Tam S, de Borja R, Tsao MS, McPherson JD. Robust global microRNA expression profiling using next-generation sequencing technologies. Lab Invest. 2014;94:350– 358.
31. Kapranov P, et al. New class of gene-termini-associated human RNAs suggests a novel RNA copying mechanism. Nature. 2010;466:642–6.
32. Lee YH, Na HS, Jeong SY, Jeong SH, Park HR, Chung J. Comparison of inflammatory microRNA expression in healthy and periodontitis tissues. Biocell. 2011;35:43–49.
33. Perri R, Nares S, Zhang S, Barros SP, Offenbacher S. MicroRNA modulation in obesity and periodontitis. J Dent Res. 2012;91:33–38.
34. Stoecklin-Wasmer C, Guarnieri P, Celenti R, Demmer RT, Kebschull M, Papapanou PN. MicroRNAs and their target genes in gingival tissues. J Dent Res. 2012;91:934– 940.
35. Xie YF, Shu R, Jiang SY, Liu DL, Zhang XL. Comparison of microRNA profiles of human periodontal diseased and healthy gingival tissues. Int J Oral Sci. 2011;3:125– 134.
36. Papapanou PN, Behle JH, Kebschull M, Celenti R, Wolf DL, Handfield M, Pavlidis P, Demmer RT. Subgingival bacterial colonization profiles correlate with gingival tissue gene expression. BMC Microbiol. 2009;9:221.
37. Garlet GP. Destructive and protective roles of cytokines in periodontitis: A re-appraisal from host defense and tissue destruction viewpoints. J Dent Res. 2010;89:1349–1363.
38. Benakanakere M, Kinane DF. Innate cellular responses to the periodontal biofilm. Front Oral Biol. 2012;15:41–55.
39. Taganov KD, Boldin MP, Chang KJ, Baltimore D. Nf-kappa B-dependent induction of microRNA mir-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA. 2006;103:12481–12486.
40. Meisgen F, Xu Landen N, Wang A, Rethi B, Bouez C, Zuccolo M, Gueniche A, Stahle M, Sonkoly E, Breton L, Pivarcsi A. miR-146a negatively regulates TLR2-induced inflammatory responses in keratinocytes. J Invest Dermatol. 2014;134:1931–1940.
41. Quinn EM, Wang JH, O'Callaghan G, Redmond HP. MicroRNA-146a is upregulated by and negatively regulates TLR2 signaling. PLoS One. 2013;8:e62232.
42. Staedel C, Darfeuille F. MicroRNAs and bacterial infection. Cell Microbiol. 2013; 15:1496–1507.
43. Elton TS, Selemon H, Elton SM, Parinandi NL. Regulation of the miR155 host gene in physiological and pathological processes. Gene. 2013;532:1–12.
44. Thompson RC, Vardinogiannis I, Gilmore TD. Identification of an NF-kappaB p50/p65-responsive site in the human miR155hg promoter. BMC Mol Biol. 2013;14:24.
45. Cremer TJ, Fatehchand K, Shah P, Gillette D, Patel H, Marsh RL, Besecker BY, Rajaram MV, Cormet-Boyaka E, Kanneganti TD, Schlesinger LS, Butchar JP, Tridandapani S. miR-155 induction by microbes/microbial ligands requires NF-kappaB-dependent de novo protein synthesis. Front Cell Infect Microbiol. 2012;2:73.
46. Cremer TJ, Ravneberg DH, Clay CD, Piper-Hunter MG, Marsh CB, Elton TS, Gunn JS, Amer A, Kanneganti TD, Schlesinger LS, Butchar JP, Tridandapani S. miR-155 induction by F. novicida but not the virulent F. tularensis results in ship down-regulation and enhanced pro-inflammatory cytokine response. PLoS One. 2009;4:e8508.
47. Hung PS, Chen FC, Kuang SH, Kao SY, Lin SC, Chang KW. miR-146a induces differentiation of periodontal ligament cells. J Dent Res. 2010;89:252–257.
48. Wang P, Hou J, Lin L, Wang C, Liu X, Li D, Ma F, Wang Z, Cao X. Inducible microRNA-155 feedback promotes type I IFN signaling in antiviral innate immunity by targeting suppressor of cytokine signaling 1. J Immunol. 2010;185:6226–6233.
49. Nowak M, Kramer B, Haupt M, Papapanou PN, Kebschull J, Hoffmann P, Schmidt-Wolf IG, Jepsen S, Brossart P, Perner S, Kebschull M. Activation of invariant NK T cells in periodontitis lesions. J Immunol. 2013;190:2282–2291.
50. Yilmaz O, Jungas T, Verbeke P, Ojcius DM. Activation of the phosphatidylinositol 3-kinase/akt pathway contributes to survival of primary epithelial cells infected with the periodontal pathogen Porphyromonas gingivalis . Infect Immun. 2004;72:3743–3751.
51. Trotta R, Chen L, Costinean S, Josyula S, Mundy-Bosse BL, Ciarlariello D, Mao C, Briercheck EL, McConnell KK, Mishra A, Yu L, Croce CM, Caligiuri MA. Overexpression of miR-155 causes expansion, arrest in terminal differentiation and functional activation of mouse natural killer cells. Blood. 2013;121:3126–3134.
52. Trotta R, Chen L, Ciarlariello D, Josyula S, Mao C, Costinean S, Yu L, Butchar JP, Tridandapani S, Croce CM, Caligiuri MA. miR-155 regulates IFN-gamma production in natural killer cells. Blood. 2012;119:3478–3485.
53. Wang P, Gu Y, Zhang Q, Han Y, Hou J, Lin L, Wu C, Bao Y, Su X, Jiang M, Wang Q, Li N, Cao X. Identification of resting and type I IFN-activated human NK cell mirnomes reveals microRNA-378 and microRNA-30e as negative regulators of NK cell cytotoxicity. J Immunol. 2012;189:211–221.
54. Huang Y, Lei Y, Zhang H, Hou L, Zhang M, Dayton AI. MicroRNA regulation of stat4 protein expression: Rapid and sensitive modulation of IL-12 signalling in human natural killer cells. Blood. 2011;118:6793–6802.
55. Chaushu S, Wilensky A, Gur C, Shapira L, Elboim M, Halftek G, Polak D, Achdout H, Bachrach G, Mandelboim O. Direct recognition of Fusobacterium nucleatum by the NK cell natural cytotoxicity receptor nkp46 aggravates periodontal disease. PLoS Pathog. 2012;8:e1002601.
56. Kramer B, Kebschull M, Nowak M, Demmer RT, Haupt M, Korner C, Perner S, Jepsen S, Nattermann J, Papapanou PN. Role of the NK cell-activating receptor CRACC in periodontitis. Infect Immun. 2013;81:690–696.
57. Pradeep AR, Manjunath SG, Swati PP, Shikha C, Sujatha PB. Gingival crevicular fluid levels of leukotriene B4 in periodontal health and disease. J Periodontol. 2007;78:2325–2330.
58. Hou J, Wang P, Lin L, Liu X, Ma F, An H, Wang Z, Cao X. MicroRNA-146a feedback inhibits RIG-i-dependent type i IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. J Immunol. 2009;183:2150–2158.
59. Ruggiero T, Trabucchi M, De Santa F, Zupo S, Harfe BD, McManus MT, Rosenfeld MG, Briata P, Gherzi R. LPS induces kh-type splicing regulatory protein-dependent processing of microRNA-155 precursors in macrophages. FASEB J. 2009;23:2898– 2908.
60. Neiva KG, Calderon NL, Alonso TR, Panagakos F, Wallet SM. Type 1 diabetes-associated TLR responsiveness of oral epithelial cells. J Dent Res. 2014;93:169–174.
61. Roush S, Slack FJ. The LET-7 family of microRNAs. Trends Cell Biol. 2008;18:505– 516.
62. Xu N, Meisgen F, Butler LM, Han G, Wang XJ, Soderberg-Naucler C, Stahle M, Pivarcsi A, Sonkoly E. MicroRNA-31 is overexpressed in psoriasis and modulates
63. inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40. J Immunol. 2013;190:678–688.
64. Song L, Lin C, Gong H, Wang C, Liu L, Wu J, Tao S, Hu B, Cheng SY, Li M, Li J. miR-486 sustains NF-kappaB activity by disrupting multiple NF-kappaB-negative feedback loops. Cell Res. 201323:274–289.
65. Zhao G, Wang B, Liu Y, Zhang JG, Deng SC, Qin Q, Tian K, Li X, Zhu S, Niu Y, Gong Q, Wang CY. MiRNA-141, downregulated in pancreatic cancer, inhibits cell proliferation and invasion by directly targeting MAP4K4. Mol Cancer Ther. 2013;12:2569–2580.
66. Tonetti MS, Imboden MA, Lang NP. Neutrophil migration into the gingival sulcus is associated with transepithelial gradients of interleukin-8 and ICAM-1. J Periodontol. 1998;69:1139–1147.
67. Kebschull M, Demmer R, Behle JH, Pollreisz A, Heidemann J, Belusko PB, Celenti R, Pavlidis P, Papapanou PN. Granulocyte chemotactic protein 2 (GCP-2/CXCL6) complements interleukin-8 in periodontal disease. J Periodontal Res. 2009;44:465– 471.
68. Yang JS, Maurin T, Robine N, Rasmussen KD, Jeffrey KL, Chandwani R, Papapetrou EP, Sadelain M, O'Carroll D, Lai EC. Conserved vertebrate miR-451 provides a platform for Dicer-independent, AGO2-mediated microRNA biogenesis. Proc Natl Acad Sci USA. 2010;107:15163–15168.
69. Havens AM, Chiu E, Taba M, Wang J, Shiozawa Y, Jung Y, Taichman LS, D'Silva NJ, Gopalakrishnan R, Wang C, Giannobile WV, Taichman RS. Stromal-derived factor-1alpha (CXCL12) levels increase in periodontal disease. J Periodontol. 2008;79:845– 853.
70. Kebschull M, Guarnieri P, Demmer RT, Boulesteix AL, Pavlidis P, Papapanou PN. Molecular differences between chronic and aggressive periodontitis. J Dent Res. 2013;92:1081–1088.
71. Smyth LA, Boardman D, Tung S, Lechler R, Lombardi G. MicroRNAs affect dendritic cells function and phenotype. Immunology. 2015;144:197-205.
72. Karrich JJ, Jachimowski LC, Libouban M, Iyer A, Brandwijk K, Taanman-Kueter EW, Nagasawa M, de Jong EC, Uittenbogaart CH, Blom B. MicroRNA-146a regulates survival and maturation of human plasmacytoid dendritic cells. Blood. 2013;122:3001– 3009.
73. Rosenberger CM, Podyminogin RL, Navarro G, Zhao GW, Askovich PS, Weiss MJ, Aderem A. miR-451 regulates dendritic cell cytokine responses to influenza infection. J Immunol. 2012;189:5965–5975.
74. Liu X, Zhan Z, Xu L, Ma F, Li D, Guo Z, Li N, Cao X. MicroRNA-148/152 impair innate response and antigen presentation of TLR-triggered dendritic cells by targeting camkiialpha. J Immunol. 2010;185:7244–7251.
75. Yuan H, Zelka S, Burkatovskaya M, Gupte R, Leeman SE, Amar S. Pivotal role of NOD2 in inflammatory processes affecting atherosclerosis and periodontal bone loss. Proc Natl Acad Sci USA. 2013;110:E5059–E5068.
76. Rebane A, Akdis CA. MicroRNAs: Essential players in the regulation of inflammation. J Allergy Clin Immunol. 2013;132:15–26.
77. Smith M, Seymour GJ, Cullinan MP. Histopathological features of chronic and aggressive periodontitis. Periodontol 2000. 2010;53:45–54.
78. Boldin MP, Taganov KD, Rao DS, Yang L, Zhao JL, Kalwani M, Garcia-Flores Y, Luong M, Devrekanli A, Xu J, Sun G, Tay J, Linsley PS, Baltimore D. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med. 2011;208:1189–1201.
79. Lindner JM, Kayo H, Hedlund S, Fukuda Y, Fukao T, Nielsen PJ. Cutting edge: The transcription factor BOB1 counteracts B cell activation and regulates miR-146a in B cells. J Immunol. 2014;192:4483–4486.
80. Mraz M, Dolezalova D, Plevova K, Stano Kozubik K, Mayerova V, Cerna K, Musilova K, Tichy B, Pavlova S, Borsky M, Verner J, Doubek M, Brychtova Y, Trbusek M, Hampl A, Mayer J, Pospisilova S. MicroRNA-650 expression is influenced by immunoglobulin gene rearrangement and affects the biology of chronic lymphocytic leukemia. Blood. 2012;119:2110–2113.
81. Seddiki N, Brezar V, Ruffin N, Levy Y, Swaminathan S. Role of miR-155 in the regulation of lymphocyte immune function and disease. Immunology. 2014;142:32– 38.
82. Lind EF, Ohashi PS. miR-155, a central modulator of T-cell responses. Eur J Immunol. 2014;44:11–15.
83. Gracias DT, Stelekati E, Hope JL, Boesteanu AC, Doering TA, Norton J, Mueller YM, Fraietta JA, Wherry EJ, Turner M, Katsikis PD. The microRNA miR-155 controls CD8(+) T cell responses by regulating interferon signaling. Nat Immunol. 2013;14:593– 602.
84. Escobar TM, Kanellopoulou C, Kugler DG, Kilaru G, Nguyen CK, Nagarajan V, Bhairavabhotla RK, Northrup D, Zahr R, Burr P, Liu X, Zhao K, Sher A, Jankovic D, Zhu J, Muljo SA. miR-155 activates cytokine gene expression in TH17 cells by regulating the DNA-binding protein JARID2 to relieve polycomb-mediated repression. Immunity. 2014;40:865–879.
85. O'Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, Chaudhuri AA, Kahn ME, Rao DS, Baltimore D. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity. 2010;33:607–619.
86. Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL. Micro-RNA-155 inhibits IFN-gamma signaling in CD4+ T cells. Eur J Immunol. 2010;40:225–231.
87. Zhao M, Wang LT, Liang GP, Zhang P, Deng XJ, Tang Q, Zhai HY, Chang CC, Su YW, Lu QJ. Up-regulation of microRNA-210 induces immune dysfunction via targeting FOXP3 in CD4 (+) T cells of psoriasis vulgaris. Clin Immunol. 2014;150:22– 30.
88. Parachuru VP, Coates DE, Milne TJ, Hussaini HM, Rich AM, Seymour GJ. Forkhead box P3-positive regulatory T-cells and interleukin 17-positive T-helper 17 cells in chronic inflammatory periodontal disease. J Periodontal Res. 2014;49:817–826.
89. Dueck A, Eichner A, Sixt M, Meister G. A miR-155-dependent microRNA hierarchy in dendritic cell maturation and macrophage activation. FEBS Lett. 2014;588:632–640.
90. Cheng P, Chen C, He HB, Hu R, Zhou HD, Xie H, Zhu W, Dai RC, Wu XP, Liao EY, Luo XH. miR-148a regulates osteoclastogenesis by targeting v-maf musculoaponeurotic fibrosarcoma oncogene homolog b. J Bone Miner Res. 2013;28:1180–1190.
91. Kapinas K, Kessler C, Ricks T, Gronowicz G, Delany AM. miR-29 modulates wnt signaling in human osteoblasts through a positive feedback loop. J Biol Chem. 2010;285:25221–25231.
92. Baglio SR, Devescovi V, Granchi D, Baldini N. MicroRNA expression profiling of human bone marrow mesenchymal stem cells during osteogenic differentiation reveals osterix regulation by mir-31. Gene. 2013;527:321–331.
93. Deng Y, Wu S, Zhou H, Bi X, Wang Y, Hu Y, Gu P, Fan X. Effects of a miR-31, RUNX2, and SATB2 regulatory loop on the osteogenic differentiation of bone mesenchymal stem cells. Stem Cells Dev. 2013;22:2278–2286.
94. Mizoguchi F, Murakami Y, Saito T, Miyasaka N, Kohsaka H. miR-31 controls osteoclast formation and bone resorption by targeting rhoa. Arthritis Res Ther. 2013;15:R102.
95. Xie Q, Wang Z, Bi X, Zhou H, Wang Y, Gu P, Fan X. Effects of miR-31 on the osteogenesis of human mesenchymal stem cells. Biochem Biophys Res Commun. 2014;446:98–104.






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