Current Stem Cell Research & TherapyCurrent Stem Cell Research & TherapyCurrent Stem Cell Research & Therapy1574-888X2212-3946Bentham Science64578310.2174/1574888X17666220617103820MedicineResearch ArticleEmerging Role of miRNAs in the Pathogenesis of PeriodontitisTaheriMohammadinfo@benthamscience.netKhoshbakhtTayyebehinfo@benthamscience.netHussenBashdarinfo@benthamscience.netAbdullahSarainfo@benthamscience.netGhafouri-FardSoudehinfo@benthamscience.netSayadArezouinfo@benthamscience.netUrology and Nephrology Research Center,, Shahid Beheshti University of Medical SciencesMen's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical SciencesDepartment of Pharmacognosy, College of Pharmacy, Hawler Medical UniversityDepartment of Pharmacology and Toxicology, College of Pharmacy, Hawler Medical University,Department of Medical Genetics, School of Medicine, S, Shahid Beheshti University of Medical SciencesDepartment of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences0104202419442744811012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/1574-888X/article/view/645783

MicroRNAs (miRNAs) have been found to participate in the pathogenesis of several immune-related conditions through the modulation of the expression of cytokine coding genes and other molecules that affect the activity of the immune system. Periodontitis is an example of these conditions associated with the dysregulation of several miRNAs. Several miRNAs such as let-7 family, miR-125, miR-378, miR-543, miR-302, miR-214, miR-200, miR-146, miR-142, miR-30 and miR-21 have been shown to be dysregulated in patients with periodontitis. miR-146 is the most assessed miRNA in these patients, which is up-regulated in most studies in patients with periodontitis. In the present review, we describe the impact of miRNAs dysregulation on the pathoetiology of periodontitis.

MicroRNAperiodontitisexpressionbiomarkerdiagnosepathogenesis.Kornman KS. Mapping the pathogenesis of periodontitis: A new look. J Periodontol 2008; 79(8s) (Suppl.): 1560-8. doi: 10.1902/jop.2008.080213 PMID: 18673011Grossi SG, Zambon JJ, Ho AW, et al. Assessment of risk for periodontal disease. I. Risk indicators for attachment loss. J Periodontol 1994; 65(3): 260-7. doi: 10.1902/jop.1994.65.3.260 PMID: 8164120Ari G, Cherukuri S, Namasivayam A. Epigenetics and periodontitis: A contemporary review. J Clin Diagn Res 2016; 10(11): ZE07-9. PMID: 28050521Zhang Y, Li Y. MicroRNAs in the regulation of immune response against infections. J Zhejiang Univ Sci B 2013; 14(1): 1-7. doi: 10.1631/jzus.B1200292 PMID: 23303626Bushati N, Cohen SM. microRNA Functions. Annu Rev Cell Dev Biol 2007; 23(1): 175-205. doi: 10.1146/annurev.cellbio.23.090506.123406 PMID: 17506695Gonçalves Fernandes J, Morford LA, Harrison PL, et al. Dysregulation of genes and microRNAs in localized aggressive periodontitis. J Clin Periodontol 2020; 47(11): 1317-25. doi: 10.1111/jcpe.13361 PMID: 32876337Asa’ad F, Garaicoa-Pazmiño C, Dahlin C, Larsson L. Expression of micrornas in periodontal and peri-implant diseases: A systematic review and meta-analysis. Int J Mol Sci 2020; 21(11): 4147. doi: 10.3390/ijms21114147 PMID: 32532036Venugopal P, Koshy T, Lavu V, et al. Differential expression of microRNAs let‐7a, miR‐125b, miR‐100, and miR‐21 and interaction with NF‐kB pathway genes in periodontitis pathogenesis. J Cell Physiol 2018; 233(8): 5877-84. doi: 10.1002/jcp.26391 PMID: 29226952Fu L, Li N, Ye Y, Ye X, Xiao T, Wu X, et al. MicroRNA Hsa-Let-7b regulates the osteogenic differentiation of human periodontal ligament stem cells by targeting CTHRC1. Stem Cells Int 2021; 5791181. doi: 10.1155/2021/5791181Du W, Wang L, Liao Z, Wang J. Circ-0085289 alleviates the progression of periodontitis by regulating let-7f-5p/SOCS6 pathway. Inflammation 2021; 44(4): 1607-19. doi: 10.1007/s10753-021-01445-8 PMID: 33710445Shen Z, Wichnieski C, Carneiro E, Garlet GP, Letra A, Silva RM. Expression profiling and functional characterization of MicroRNAs in apical periodontitis. J Endod 2021; 47(2): 263-71. doi: 10.1016/j.joen.2020.11.016 PMID: 33245973Li J, Wang M, Song L, Wang X, Lai W, Jiang S. Lnc RNA MALAT 1 regulates inflammatory cytokine production in lipopolysaccharide‐stimulated human gingival fibroblasts through sponging miR‐20a and activating TLR 4 pathway. J Periodontal Res 2020; 55(2): 182-90. doi: 10.1111/jre.12700 PMID: 31552681Sun KT, Chen MYC, Tu MG, Wang IK, Chang SS, Li CY. MicroRNA-20a regulates autophagy related protein-ATG16L1 in hypoxia-induced osteoclast differentiation. Bone 2015; 73: 145-53. doi: 10.1016/j.bone.2014.11.026 PMID: 25485521Wang X, Wang Y. LncRNA DCST1‐AS1 inhibits PDLCs’ proliferation in periodontitis and may bind with miR‐21 precursor to upregulate PLAP‐1. J Periodontal Res 2021; 56(2): 256-64. doi: 10.1111/jre.12809 PMID: 33533513Wei F, Liu D, Feng C, et al. microRNA-21 mediates stretch-induced osteogenic differentiation in human periodontal ligament stem cells. Stem Cells Dev 2015; 24(3): 312-9. doi: 10.1089/scd.2014.0191 PMID: 25203845Zhou W, Su L, Duan X, et al. MicroRNA-21 down-regulates inflammation and inhibits periodontitis. Mol Immunol 2018; 101: 608-14. doi: 10.1016/j.molimm.2018.05.008 PMID: 29884447Lee NH, Lee E, Kim YS, Kim WK, Lee YK, Kim SH. Differential expression of microRNAs in the saliva of patients with aggressive periodontitis: A pilot study of potential biomarkers for aggressive periodontitis. J Periodontal Implant Sci 2020; 50(5): 281-90. doi: 10.5051/jpis.2000120006 PMID: 33124206Zhang Z, Shuai Y, Zhou F, et al. PDLSCs regulate angiogenesis of periodontal ligaments via VEGF transferred by exosomes in periodontitis. Int J Med Sci 2020; 17(5): 558-67. doi: 10.7150/ijms.40918 PMID: 32210705Coêlho MC, Queiroz IC. viana JMC. Aquino SGd, Persuhn DC, Oliveira NFPd. miR-9-1 gene methylation and DNMT3B (rs2424913) polymorphism may contribute to periodontitis. J Appl Oral Sci 2020; 28: e20190583.Silva-Sousa AC, Mazzi-Chaves JF, Freitas JV, et al. Association between estrogen, vitamin D and microRNA17 gene polymorphisms and periapical lesions. Braz Dent J 2020; 31(1): 19-24. doi: 10.1590/0103-644020200 PMID: 32159700Li L, Liu W, Wang H, et al. Mutual inhibition between HDAC9 and miR-17 regulates osteogenesis of human periodontal ligament stem cells in inflammatory conditions. Cell Death Dis 2018; 9(5): 480. doi: 10.1038/s41419-018-0480-6 PMID: 29691366Chen N, Sui BD, Hu CH, et al. microRNA-21 contributes to orthodontic tooth movement. J Dent Res 2016; 95(12): 1425-33. doi: 10.1177/0022034516657043 PMID: 27422860Zheng M, Guo J. Nicotinamide‐induced silencing of SIRT1 by miR‐22‐3p increases periodontal ligament stem cell proliferation and differentiation. Cell Biol Int 2020; 44(3): 764-72. doi: 10.1002/cbin.11271 PMID: 31769563Zhang Y, Li S, Yuan S, Zhang H, Liu J. MicroRNA-23a inhibits osteogenesis of periodontal mesenchymal stem cells by targeting bone morphogenetic protein signaling. Arch Oral Biol 2019; 102: 93-100. doi: 10.1016/j.archoralbio.2019.04.001 PMID: 30981077Li Z, Sun Y, Cao S, Zhang J, Wei J. Downregulation of miR‐24‐3p promotes osteogenic differentiation of human periodontal ligament stem cells by targeting SMAD family member 5. J Cell Physiol 2019; 234(5): 7411-9. doi: 10.1002/jcp.27499 PMID: 30378100Zhang K, Geng Y, Wang S, Huo L. MicroRNA-26a-5p targets Wnt5a to regulate osteogenic differentiation of human periodontal ligament stem cell from inflammatory microenvironment Zhonghua kou qiang yi xue za zhi 2019; 54(10): 662-9.Liu Y, Liu C, Zhang A, et al. Down-regulation of long non-coding RNA MEG3 suppresses osteogenic differentiation of periodontal ligament stem cells (PDLSCs) through miR-27a-3p/IGF1 axis in periodontitis. Aging (Albany NY) 2019; 11(15): 5334-50. doi: 10.18632/aging.102105 PMID: 31398715Liu X, Yang B, Zhang Y, et al. miR-30a-5p inhibits osteogenesis and promotes periodontitis by targeting Runx2. BMC Oral Health 2021; 21(1): 513. doi: 10.1186/s12903-021-01882-9 PMID: 34635105Wu L, Yang K, Gui Y, Wang X. Nicotine-upregulated miR-30a arrests cell cycle in G1 phase by directly targeting CCNE2 in human periodontal ligament cells. Biochem Cell Biol 2020; 98(3): 354-61. doi: 10.1139/bcb-2019-0156 PMID: 31689122Wang L, He Y, Ning W. Role of enhancer of zeste homolog 2 in osteoclast formation and periodontitis development by downregulating microRNA‐101‐regulated VCAM‐1. J Tissue Eng Regen Med 2021; 15(6): 534-45. doi: 10.1002/term.3187 PMID: 33686766Liu M, Liu Q, Fan S, et al. LncRNA LTSCCAT promotes tongue squamous cell carcinoma metastasis via targeting the miR-103a-2-5p/SMYD3/TWIST1 axis. Cell Death Dis 2021; 12(2): 144. doi: 10.1038/s41419-021-03415-2 PMID: 33542221He F, Zhou Y, Wang X, et al. Functional polymorphisms of ctla4 associated with aggressive periodontitis in the chinese han population. Cell Physiol Biochem 2018; 50(3): 1178-85. doi: 10.1159/000494544 PMID: 30355938Jia B, Qiu X, Chen J, et al. A feed‐forward regulatory network lncPCAT1/miR‐106a‐5p/E2F5 regulates the osteogenic differentiation of periodontal ligament stem cells. J Cell Physiol 2019; 234(11): 19523-38. doi: 10.1002/jcp.28550 PMID: 30997692He W, Zhang N, Lin Z. MicroRNA-125a-5p modulates macrophage polarization by targeting E26 transformation-specific variant 6 gene during orthodontic tooth movement. Arch Oral Biol 2021; 124: 105060. doi: 10.1016/j.archoralbio.2021.105060 PMID: 33524878Dong Y, Li P, Ni Y, Zhao J, Liu Z. Decreased microRNA-125a-3p contributes to upregulation of p38 MAPK in rat trigeminal ganglions with orofacial inflammatory pain. PLoS One 2014; 9(11): e111594. doi: 10.1371/journal.pone.0111594 PMID: 25380251Wang Y, Lv F, Huang L, et al. Human amnion-derived mesenchymal stem cells promote osteogenic differentiation of lipopolysaccharide-induced human bone marrow mesenchymal stem cells via ANRIL/miR-125a/APC axis. Stem Cell Res Ther 2021; 12(1): 35. doi: 10.1186/s13287-020-02105-8 PMID: 33413674Venugopal P, Lavu V, Rao SR, Venkatesan V. Association of microRNA-125a and microRNA-499a polymorphisms in chronic periodontitis in a sample south Indian population: A hospital-based genetic association study. Gene 2017; 631: 10-5. doi: 10.1016/j.gene.2017.07.053 PMID: 28732738Xue N, Qi L, Zhang G, Zhang Y. miRNA-125b regulates osteogenic differentiation of periodontal ligament cells through NKIRAS2/NF-κB pathway. Cell Physiol Biochem 2018; 48(4): 1771-81. doi: 10.1159/000492350 PMID: 30078007Mu Y, Deng J, Li J, Song L, Jiang S. Regulatory effect of microRNA-126 on macrophage proliferation caused by high glucose stimulation. Zhonghua kou Qiang yi xue za zhi= Zhonghua Kouqiang Yixue Zazhi= Chinese Journal of Stomatology 2020; 55(12): 969-75.Wu Y, Song LT, Li JS, Zhu DW, Jiang SY, Deng JY. MicroRNA‐126 regulates inflammatory cytokine secretion in human gingival fibroblasts under high glucose via targeting tumor necrosis factor receptor associated factor 6. J Periodontol 2017; 88(11): e179-87. doi: 10.1902/jop.2017.170091 PMID: 28598282Mahendra J, Mahendra L, Fageeh HN, et al. miRNA-146a and miRNA-126 as potential biomarkers in patients with coronary artery disease and generalized periodontitis. Materials (Basel) 2021; 14(16): 4692. doi: 10.3390/ma14164692 PMID: 34443215Na HS, Park MH, Song YR, et al. Elevated microRNA‐128 in periodontitis mitigates tumor necrosis factor‐α response via p38 signaling pathway in macrophages. J Periodontol 2016; 87(9): e173-82. doi: 10.1902/jop.2016.160033 PMID: 27240473Yu M, Chi C. lncRNA FGD5-AS1 and miR-130a Can Be Used for Prognosis Analysis of Patients with Chronic Periodontitis. BioMed Res Int 2021.Xu Y, Ren C, Zhao X, Wang W, Zhang N. microRNA-132 inhibits osteogenic differentiation of periodontal ligament stem cells via GDF5 and the NF-κB signaling pathway. Pathol Res Pract 2019; 215(12): 152722. doi: 10.1016/j.prp.2019.152722 PMID: 31718857Han Y, Wang F, Shao L, Huang P, Xu Y. LncRNA TUG1 mediates lipopolysaccharide-induced proliferative inhibition and apoptosis of human periodontal ligament cells by sponging miR-132. Acta Biochim Biophys Sin (Shanghai) 2019; 51(12): gmz125. doi: 10.1093/abbs/gmz125 PMID: 31735958Han P, Bartold PM, Salomon C, Ivanovski S. Salivary small extracellular vesicles associated miRNAs in periodontal status—A pilot study. Int J Mol Sci 2020; 21(8): 2809. doi: 10.3390/ijms21082809 PMID: 32316600Rovas A, Puriene A, Snipaitiene K, Punceviciene E, Buragaite-Staponkiene B, Matuleviciute R, et al. Gingival crevicular fluid microRNA associations with periodontitis. J Oral Sci 2021; 64(1): 11-6. PMID: 34690249Zhou X, Luan X, Chen Z, et al. MicroRNA-138 inhibits periodontal progenitor differentiation under inflammatory conditions. J Dent Res 2016; 95(2): 230-7. doi: 10.1177/0022034515613043 PMID: 26518300Li S, Song Z, Dong J, Shu R. microRNA-142 is upregulated by tumor necrosis factor-alpha and triggers apoptosis in human gingival epithelial cells by repressing BACH2 expression. Am J Transl Res 2017; 9(1): 175-83. PMID: 28123644Chen H, Lan Z, Li Q, Li Y. Abnormal expression of long noncoding RNA FGD5-AS1 affects the development of periodontitis through regulating miR-142-3p/SOCS6/NF-κB pathway. Artif Cells Nanomed Biotechnol 2019; 47(1): 2098-106. doi: 10.1080/21691401.2019.1620256 PMID: 31144533Dong Y, Feng S, Dong F. Maternally-Expressed Gene 3 (MEG3)/miR-143-3p Regulates Injury to Periodontal Ligament Cells by Mediating the AKT/Inhibitory κB Kinase (IKK) Pathway. Med Sci Monit 2020; 26: e922486-1. doi: 10.12659/MSM.922486 PMID: 32520926Nisha KJ, Janam P, Harshakumar K. Identification of a novel salivary biomarker miR‐143‐3p for periodontal diagnosis: A proof of concept study. J Periodontol 2019; 90(10): 1149-59. doi: 10.1002/JPER.18-0729 PMID: 31021403Li J, Wang R, Ge Y, Chen D, Wu B, Fang F. Assessment of microRNA‐144‐5p and its putative targets in inflamed gingiva from chronic periodontitis patients. J Periodontal Res 2019; 54(3): 266-77. doi: 10.1111/jre.12627 PMID: 30450635Ghotloo S, Motedayyen H, Amani D, Saffari M, Sattari M. Assessment of microRNA-146a in generalized aggressive periodontitis and its association with disease severity. J Periodontal Res 2019; 54(1): 27-32. doi: 10.1111/jre.12538 PMID: 30328616Zhao S, Cheng Y, Kim JG. microRNA‐146a downregulates IL‐17 and IL‐35 and inhibits proliferation of human periodontal ligament stem cells. J Cell Biochem 2019; 120(8): 13861-6. doi: 10.1002/jcb.28659 PMID: 30989711Lina S, Lihong Q, Di Y, Bo Y, Xiaolin L, Jing M. microRNA‐146a and Hey2 form a mutual negative feedback loop to regulate the inflammatory response in chronic apical periodontitis. J Cell Biochem 2019; 120(1): 645-57. doi: 10.1002/jcb.27422 PMID: 30125982Wang Y, Wei Z, Xia T, Shi B. MicroRNA-146a downregulates interleukin-13 and inhibits the proliferation of human periodontal ligament stem cells. Arch Oral Biol 2021; 129: 105165. doi: 10.1016/j.archoralbio.2021.105165 PMID: 34146927Tang L, Li X, Bai Y, Wang P, Zhao Y. MicroRNA‐146a negatively regulates the inflammatory response to Porphyromonas gingivalis in human periodontal ligament fibroblasts via TRAF6/p38 pathway. J Periodontol 2019; 90(4): 391-9. doi: 10.1002/JPER.18-0190 PMID: 30378773Sattari M, Taheri RA. ArefNezhad R, Motedayyen H. The expression levels of MicroRNA-146a, RANKL and OPG after non-surgical periodontal treatment. BMC Oral Health 2021; 21(1): 523. doi: 10.1186/s12903-021-01883-8 PMID: 33388028Yagnik K, Mahendra J, Kurian VM. The Periodontal‐Cardiovascular alliance: Evaluation of miRNA‐146a in subgingival plaque samples of chronic periodontitis patients with and without coronary heart disease. J Investig Clin Dent 2019; 10(4): e12442. doi: 10.1111/jicd.12442 PMID: 31338994Bagavad Gita J, George AV, Pavithra N, Chandrasekaran SC, Latchumanadhas K, Gnanamani A. Dysregulation of miR-146a by periodontal pathogens: A risk for acute coronary syndrome. J Periodontol 2019; 90(7): 756-65. doi: 10.1002/JPER.18-0466 PMID: 30618100Gao Y, Hao C. Expression of miR-146a in saliva of chronic periodontitis patients and its influence on gingival crevicular inflammation and MMP-8/TIMP-1 levels. Shanghai Kou Qiang Yi Xue 2018; 27(3): 309-12.Jiang S, Hu Y, Deng S, et al. miR-146a regulates inflammatory cytokine production in Porphyromonas gingivalis lipopolysaccharide-stimulated B cells by targeting IRAK1 but not TRAF6. Biochim Biophys Acta Mol Basis Dis 2018; 1864(3): 925-33. doi: 10.1016/j.bbadis.2017.12.035 PMID: 29288795Motedayyen H, Ghotloo S, Saffari M, Sattari M, Amid R. Evaluation of microRNA‐146a and its targets in gingival tissues of patients with chronic periodontitis. J Periodontol 2015; 86(12): 1380-5. doi: 10.1902/jop.2015.150319 PMID: 26313020Xie YF, Shu R, Jiang SY, Liu DL, Ni J, Zhang XL. MicroRNA-146 inhibits pro-inflammatory cytokine secretion through IL-1 receptor-associated kinase 1 in human gingival fibroblasts. J Inflamm (Lond) 2013; 10(1): 20. doi: 10.1186/1476-9255-10-20 PMID: 23680172Sanada T, Sano T, Sotomaru Y, et al. Anti-inflammatory effects of miRNA-146a induced in adipose and periodontal tissues. Biochem Biophys Rep 2020; 22: 100757. doi: 10.1016/j.bbrep.2020.100757 PMID: 32346618Xu R, Zeng G, Wang S, et al. Periodontitis promotes the diabetic development of obese rat via miR-147 induced classical macrophage activation. Biomed Pharmacother 2016; 83: 892-7. doi: 10.1016/j.biopha.2016.07.030 PMID: 27518498Bao L, Zhang X, Xu Y, et al. Dysfunction of mir-148a-nrp1 functional axis suppresses osteogenic differentiation of periodontal ligament stem cells under inflammatory microenvironment. Cell Reprogram 2019; 21(6): 314-22. doi: 10.1089/cell.2019.0026 PMID: 31809209Wu D, Ma L. Downregulating microRNA-152-3p promotes the viability and osteogenic differentiation of periodontal ligament stem cells via targeting integrin alpha 5. Arch Oral Biol 2020; 120: 104930. doi: 10.1016/j.archoralbio.2020.104930 PMID: 33059275Jiang H, Jia P. MiR‐153‐3p inhibits osteogenic differentiation of periodontal ligament stem cells through KDM6A‐induced demethylation of H3K27me3. J Periodontal Res 2021; 56(2): 379-87. doi: 10.1111/jre.12830 PMID: 33368310Mahendra J, Mahendra L, Mugri MH, et al. Role of periodontal bacteria, viruses, and placental mir155 in chronic periodontitis and preeclampsia—a genetic microbiological study. Curr Issues Mol Biol 2021; 43(2): 831-44. doi: 10.3390/cimb43020060 PMID: 34449559Wang X, Sun H, Liao H, et al. MicroRNA-155-3p mediates TNF-α-inhibited cementoblast differentiation. J Dent Res 2017; 96(12): 1430-7. doi: 10.1177/0022034517718790 PMID: 28692806Zheng Y, Dong C, Yang J, et al. Exosomal microRNA‐155‐5p from PDLSCs regulated Th17/Treg balance by targeting sirtuin‐1 in chronic periodontitis. J Cell Physiol 2019; 234(11): 20662-74. doi: 10.1002/jcp.28671 PMID: 31016751Roganović JR. microRNA‐146a and ‐155, upregulated by periodontitis and type 2 diabetes in oral fluids, are predicted to regulate SARS‐CoV‐2 oral receptor genes. J Periodontol 2021; 92(7): 35-43. doi: 10.1002/JPER.20-0623 PMID: 33336412Radović N, Nikolić Jakoba N, Petrović N, Milosavljević A, Brković B, Roganović J. MicroRNA-146a and microRNA-155 as novel crevicular fluid biomarkers for periodontitis in non-diabetic and type 2 diabetic patients. J Clin Periodontol 2018; 45(6): 663-71. doi: 10.1111/jcpe.12888 PMID: 29517812Al-Rawi NH, Al-Marzooq F, Al-Nuaimi AS, Hachim MY, Hamoudi R. Salivary microRNA 155, 146a/b and 203: A pilot study for potentially non-invasive diagnostic biomarkers of periodontitis and diabetes mellitus. PLoS One 2020; 15(8): e0237004. doi: 10.1371/journal.pone.0237004 PMID: 32756589Wu P, Feng J, Wang W. Expression of miR-155 and miR-146a in the saliva of patients with periodontitis and its clinical value. Am J Transl Res 2021; 13(6): 6670-7. PMID: 34306411Molteni M, Bosi A, Rossetti C. The effect of cyanobacterial LPS antagonist (CyP) on cytokines and micro-RNA expression Induced by Porphyromonas gingivalis LPS. Toxins (Basel) 2018; 10(7): 290. doi: 10.3390/toxins10070290 PMID: 30012943Wang X, Sun H, Liu H, et al. MicroRNA‐181b‐5p modulates tumor necrosis factor‐α‐induced inflammatory responses by targeting interleukin‐6 in cementoblasts. J Cell Physiol 2019; 234(12): 22719-30. doi: 10.1002/jcp.28837 PMID: 31131439Lv P, Gao P, Tian G, et al. Osteocyte-derived exosomes induced by mechanical strain promote human periodontal ligament stem cell proliferation and osteogenic differentiation via the miR-181b-5p/PTEN/AKT signaling pathway. Stem Cell Res Ther 2020; 11(1): 295. doi: 10.1186/s13287-020-01815-3 PMID: 32680565Wang L, Wu F, Song Y, Li X, Wu Q, Duan Y, et al. Long noncoding RNA related to periodontitis interacts with miR-182 to upregulate osteogenic differentiation in periodontal mesenchymal stem cells of periodontitis patients. Cell Death Dis 2016; 7(8): e2327. doi: 10.1038/cddis.2016.125Rovas A, Puriene A, Snipaitiene K, et al. Analysis of periodontitis-associated miRNAs in gingival tissue, gingival crevicular fluid, saliva and blood plasma. Arch Oral Biol 2021; 126: 105125. doi: 10.1016/j.archoralbio.2021.105125 PMID: 33862403Venugopal P, Lavu V. RangaRao S, Venkatesan V. RangaRao S, Venkatesan V. Evaluation of a panel of single-nucleotide polymorphisms in miR-146a and miR-196a2 genomic regions in patients with chronic periodontitis. Genet Test Mol Biomarkers 2017; 21(4): 228-35. doi: 10.1089/gtmb.2016.0358 PMID: 28384038Li M, Wei L, Zhou W, He Z, Ran S, Liang J. miR-200a contributes to the migration of BMSCs induced by the secretions of E. faecalis via FOXJ1/NFκB/MMPs axis. Stem Cell Res Ther 2020; 11(1): 317. doi: 10.1186/s13287-020-01833-1 PMID: 31900237Akkouch A, Zhu M, Romero-Bustillos M, et al. MicroRNA-200c attenuates periodontitis by modulating proinflammatory and osteoclastogenic mediators. Stem Cells Dev 2019; 28(15): 1026-36. doi: 10.1089/scd.2019.0027 PMID: 31017046Krongbaramee T, Zhu M, Qian Q, et al. Plasmid encoding microRNA-200c ameliorates periodontitis and systemic inflammation in obese mice. Mol Ther Nucleic Acids 2021; 23: 1204-16. doi: 10.1016/j.omtn.2021.01.030 PMID: 33664998Hong L, Sharp T, Khorsand B, et al. MicroRNA-200c represses IL-6, IL-8, and CCL-5 expression and enhances osteogenic differentiation. PLoS One 2016; 11(8): e0160915. doi: 10.1371/journal.pone.0160915 PMID: 27529418Matsui S, Zhou L, Nakayama Y, et al. MiR-200b attenuates IL-6 production through IKKβ and ZEB1 in human gingival fibroblasts. Inflamm Res 2018; 67(11-12): 965-73. doi: 10.1007/s00011-018-1192-1 PMID: 30306207Kalea AZ, Hoteit R, Suvan J, et al. Upregulation of gingival tissue miR-200b in obese periodontitis subjects. J Dent Res 2015; 94(3-suppl): 59S-69S. doi: 10.1177/0022034514568197 PMID: 25630869Elazazy O, Amr K, Abd El Fattah A, Abouzaid M. Evaluation of serum and gingival crevicular fluid microRNA-223, microRNA-203 and microRNA-200b expression in chronic periodontitis patients with and without diabetes type 2. Arch Oral Biol 2021; 121: 104949. doi: 10.1016/j.archoralbio.2020.104949 PMID: 33157494Li J, Li L, Wang X, Xiao L. Porphyromonas gingivalis inhibition of MicroRNA-205-5p expression modulates proinflammatory cytokines in gingival epithelial cells. Biochem Genet 2020; 58(4): 566-79. doi: 10.1007/s10528-020-09957-y PMID: 32303947Tomofuji T, Yoneda T, Machida T, et al. MicroRNAs as serum biomarkers for periodontitis. J Clin Periodontol 2016; 43(5): 418-25. doi: 10.1111/jcpe.12536 PMID: 26910654Pizzicannella J, Cavalcanti M, Trubiani O, Diomede F. MicroRNA 210 mediates VEGF upregulation in human periodontal ligament stem cells cultured on 3Dhydroxyapatite ceramic scaffold. Int J Mol Sci 2018; 19(12): 3916. doi: 10.3390/ijms19123916 PMID: 30563289Hua B, Xiang J, Guo L, Lu D. MicroRNA-212-5p regulates the inflammatory response of periodontal ligament cells by targeting myeloid differentiation factor 88. Arch Oral Biol 2020; 118: 104831. doi: 10.1016/j.archoralbio.2020.104831 PMID: 32707140Feng Y, Wan P, Yin L. Long noncoding RNA X-inactive specific transcript (XIST) promotes osteogenic differentiation of periodontal ligament stem cells by sponging microRNA-214-3p. Med Sci Monit 2020; 26: e918932-1. doi: 10.12659/MSM.918932 PMID: 32057034Ou L, Sun T, Cheng Y, et al. MicroRNA‐214 contributes to regulation of necroptosis via targeting ATF4 in diabetes‐associated periodontitis. J Cell Biochem 2019; 120(9): 14791-803. doi: 10.1002/jcb.28740 PMID: 31090954Yao S, Zhao W, Ou Q, Liang L, Lin X, Wang Y. MicroRNA-214 suppresses osteogenic differentiation of human periodontal ligament stem cells by targeting ATF4. Stem Cells Int 2017. doi: 10.1155/2017/3028647Cao F, Zhan J, Chen X, Zhang K, Lai R, Feng Z. miR-214 promotes periodontal ligament stem cell osteoblastic differentiation by modulating Wnt/β-catenin signaling. Mol Med Rep 2017; 16(6): 9301-8. doi: 10.3892/mmr.2017.7821 PMID: 29152645Guo J, Zeng X, Miao J, et al. Expression of concern: MiRNA‐218 regulates osteoclast differentiation and inflammation response in periodontitis rats through Mmp9. Cell Microbiol 2019; 21(4): e12979. doi: 10.1111/cmi.12979 PMID: 30444938Wu D, Yin L, Sun D, et al. Long noncoding RNA TUG1 promotes osteogenic differentiation of human periodontal ligament stem cell through sponging microRNA-222-3p to negatively regulate Smad2/7. Arch Oral Biol 2020; 117: 104814. doi: 10.1016/j.archoralbio.2020.104814 PMID: 32574885Zhang S, Li C, Liu J, et al. Fusobacterium nucleatum promotes epithelial‐mesenchymal transiton through regulation of the lncRNA MIR4435‐2HG/miR‐296‐5p/Akt2/SNAI1 signaling pathway. FEBS J 2020; 287(18): 4032-47. doi: 10.1111/febs.15233 PMID: 31997506Irwandi RA, Khonsuphap P, Limlawan P, Vacharaksa A. miR‐302a‐3p regulates RANKL expression in human mandibular osteoblast‐like cells. J Cell Biochem 2018; 119(6): 4372-81. doi: 10.1002/jcb.26456 PMID: 29058810Duan Y, An W, Wu Y, Wang J. Tetramethylpyrazine reduces inflammation levels and the apoptosis of LPS stimulated human periodontal ligament cells via the downregulation of miR 302b. Int J Mol Med 2020; 45(6): 1918-26. doi: 10.3892/ijmm.2020.4554 PMID: 32236610Wang Y, Li Y, Shao P, Wang L, Bao X, Hu M. IL1β inhibits differentiation of cementoblasts via microRNA‐325‐3p. J Cell Biochem 2020; 121(3): 2606-17. doi: 10.1002/jcb.29482 PMID: 31680324Wang Z, Wang D, Guo S, Zhuo Q, Jiang D, Yu Z. Long noncoding RNA distal-less homeobox 2 antisense 1 restrains inflammatory response and apoptosis of periodontal ligament cells by binding with microRNA-330-3p to regulate Ro60, Y RNA binding protein. Arch Oral Biol 2022; 133: 105298. doi: 10.1016/j.archoralbio.2021.105298 PMID: 34752991Lian J, Wu X, Liu Y, et al. Potential roles of miR‐335‐5p on pathogenesis of experimental periodontitis. J Periodontal Res 2020; 55(2): 191-8. doi: 10.1111/jre.12701 PMID: 31541471Yue J, Wang P, Hong Q, et al. MicroRNA-335-5p plays dual roles in periapical lesions by complex regulation pathways. J Endod 2017; 43(8): 1323-8. doi: 10.1016/j.joen.2017.03.018 PMID: 28578884Mueller R, Bajric D, Keceli HG, et al. hsa‐miR‐374b‐5p regulates expression of the gene U2AF homology motif (UHM) kinase 1. J Periodontal Res 2021; 56(6): 1028-36. doi: 10.1111/jre.12913 PMID: 34160076Wang J, Du C, Xu L. Circ-0081572 inhibits the progression of periodontitis through regulating the miR-378h/RORA axis. Arch Oral Biol 2021; 124: 105053. doi: 10.1016/j.archoralbio.2021.105053 PMID: 33524877Zhou H, Li X, Wu RX, et al. Periodontitis‐compromised dental pulp stem cells secrete extracellular vesicles carrying miRNA‐378a promote local angiogenesis by targeting Sufu to activate the Hedgehog/Gli1 signalling. Cell Prolif 2021; 54(5): e13026. doi: 10.1111/cpr.13026 PMID: 33759282Ma L, Wu D. MicroRNA-383-5p regulates osteogenic differentiation of human periodontal ligament stem cells by targeting histone deacetylase 9. Arch Oral Biol 2021; 129: 105166. doi: 10.1016/j.archoralbio.2021.105166 PMID: 34118749Huang N, Li C, Sun W, Wu J, Xiao F. Long non‐coding RNA TUG1 participates in LPS‐induced periodontitis by regulating miR‐498/RORA pathway. Oral Dis 2021; 27(3): 600-10. doi: 10.1111/odi.13590 PMID: 32762066Kadkhodazadeh M, Jafari AR, Amid R, et al. MiR146a and MiR499 gene polymorphisms in Iranian periodontitis and peri-implantitis patients. J Long Term Eff Med Implants 2013; 23(1): 9-16. doi: 10.1615/JLongTermEffMedImplants.2013007073 PMID: 24266439Zhou M, Hu H, Han Y, et al. Long non‐coding RNA 01126 promotes periodontitis pathogenesis of human periodontal ligament cells via miR‐518a‐5p/HIF‐1α/MAPK pathway. Cell Prolif 2021; 54(1): e12957. doi: 10.1111/cpr.12957 PMID: 33231338Li W, Wang J, Hao W, Yu C. MicroRNA-543-3p down-regulates inflammation and inhibits periodontitis through KLF6. Biosci Rep 2021; 41(5): BSR20210138. doi: 10.1042/BSR20210138 PMID: 33955459Ge Y, Li J, Hao Y, et al. MicroRNA-543 functions as an osteogenesis promoter in human periodontal ligament-derived stem cells by inhibiting transducer of ERBB2, 2. J Periodontal Res 2018; 53(5): 832-41. doi: 10.1111/jre.12572 PMID: 29851072Li J, Xie R. Circular RNA expression profile in gingival tissues identifies circ-0062491 and circ-0095812 as potential treatment targets. J Cell Biochem 2019; 120(9): 14867-74. doi: 10.1002/jcb.28748 PMID: 31021476Shao Q, Liu S, Zou C, Ai Y. Effect of LSD1 on osteogenic differentiation of human periodontal ligament stem cells in periodontitis 2021. Oral Dis 2021; odi.14066. doi: 10.1111/odi.14066 PMID: 34739163Yang J, Zhou J, Cui B, Yu T. Evaluation of hypoxia on the expression of miR-646/IGF-1 signaling in human periodontal ligament cells (hPDLCs). Med Sci Monit 2018; 24: 5282-91. doi: 10.12659/MSM.910163 PMID: 30058629Peng 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 Commun 2018; 503(2): 815-21. doi: 10.1016/j.bbrc.2018.06.081 PMID: 29913147Chen Q, Cao M, Ge H. Knockdown of MALAT1 inhibits the progression of chronic periodontitis via targeting miR-769-5p/HIF3A axis. BioMed Res Int 2021.Huang Y, Han Y, Guo R, et al. Long non-coding RNA FER1L4 promotes osteogenic differentiation of human periodontal ligament stromal cells via miR-874-3p and vascular endothelial growth factor A. Stem Cell Res Ther 2020; 11(1): 5. doi: 10.1186/s13287-019-1519-z PMID: 31900200Du Y, Qi Y, Chen H, Shen G. The expression and clinical significance of miR-1226 in patients with periodontitis. BMC Oral Health 2021; 21(1): 487. doi: 10.1186/s12903-021-01855-y PMID: 34592963Micó-Martínez P, García-Giménez J, Seco-Cervera M, et al. miR-1226 detection in GCF as potential biomarker of chronic periodontitis: A pilot study. Med Oral Patol Oral Cir Bucal 2018; 23(3): 0. doi: 10.4317/medoral.22329 PMID: 29680855Liu Y, Yang J, Sun W. Upregulation of IL-10 expression inhibits the proliferation of human periodontal ligament stem cells. Braz Oral Res 2020; 34: e030. doi: 10.1590/1807-3107bor-2020.vol34.0030 PMID: 32236319