MicroRNAs in oral fluids (saliva and gingival crevicular fluid) as biomarkers in orthodontics: systematic review and integrated bioinformatic analysis

Abstract

Background MicroRNAs (miRNAs) are non-coding short, single-stranded RNA molecules that may serve as biomarkers for various inflammatory and molecular mechanisms underlying bone and tissue remodeling consequent to orthodontic force application. Methods A thorough literature search in major databases was conducted in March 2021 to generate evidence for miRNAs in orthodontics, with prior PROSPERO registration. The initial search revealed 920 articles, subjected to strict selection criteria according to PRISMA, and resulted in final inclusion of four studies. Quality assessment by QUADAS-2 classified three studies as unclear risk-of-bias while the applicability was high. Further, bioinformatic analysis was performed to identify the target genes from the miRNA database (miRDB) and TargetScan databases and their protein-protein interaction pathways with the STRING analysis. Results Multiple miRNAs in gingival crevicular fluid (GCF) of orthodontic patients were seen, including miRNA-21, 27(a/b), 29(a/b/c), 34,146(a/b), 101, and 214 along with matrix metalloproteinases (MMPs)-1, 2, 3, 8, 9, 14 in one study. A statistically significant increase in expression of miRNA-29a/b/c,101, 21 from pre-treatment (before initiation of retraction) was seen to reach a peak at 4–6 weeks (wk) of retraction. On the contrary, miRNA-34a showed downregulation from the 1 day to 4 wk of retraction and also, negatively correlated with MMPs-2,9,14 levels at the same observation times. The distance of canine movement showed mild correlation with miRNA-27a/b, 214 at 2 wk of retraction. Bioinformatics revealed 1213 mutual target genes which were analyzed for inter-relational pathways using Cytoscape plugin, MCODE. Further, 894 prominent protein interactions were identified from the STRING database and SMAD4, IGF1, ADAMTS6, COL4A1, COL1A1, COL3A1, FGFR1, COL19A1, FBN1, COL5A1, MGAT4A, LTBP1, MSR1, COL11A1, and COL5A3 were recognized as the hub genes. Their interactions were able to isolate multiple miRNAs: hsa-miR-34a-5p, hsa-miR-29b-2-5p, hsa-miR-29b-3p, hsa-miR-34a-3p, hsa-miR-27a-5p, hsa-miR-29a-5p, hsa-miR-29b-1-5p, hsa-miR-29c-3p, hsa-miR-214-5p, hsa-miR-27a-3p, hsa-miR-29a-3p, hsamiR-146-5p, which were found promising as biomarkers for tooth movement. Conclusions Our results support using miRNAs as biomarkers in varied orthodontic study designs and for inter-relationships with pathological settings like periodontal disease, pre-malignancies, or conditions like obesity or metabolic irregularities, etc. The identified target genes and their protein interaction pathways can be used to propose precision therapies, focusing on ideal tooth movement with minimal iatrogenic side-effects.

MicroRNA Modulation during Orthodontic Tooth Movement: A Promising Strategy for Novel Diagnostic and Personalized Therapeutic Interventions

“…In a recent 2021 review of the literature [ 30 ], Kapoor et al highlighted miRNAs correlated with a specific teeth movement: canine retraction (through CGF samples).…”

“…In this regard, molecular biology also makes its contribution to this field of dentistry, thanks to the study of the modulation of miRNAs during OTM. In particular, what appears to be their function during certain tooth movements [ 30 , 31 , 32 , 33 , 34 ] or their role in the modulation of biological mechanisms [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ] can provide a fundamental tool to the future orthodontists for a new approach to the techniques that exist in this field of dentistry. However, the expression of miRNAs during orthodontic movements remains to be further investigated.…”

Roles of Non-Coding RNAs in Primary Biliary Cholangitis

“…Studies on ncRNAs in human biology have gained much interest in the scientific world in recent years (Kapoor et al, 2021;Makkos et al, 2021;Wang et al, 2021). The role of ncRNAs in immune regulation, inflammation and autoimmunity can be of significant translational implication in medicine.…”

ADAMTS6: Emerging roles in cardiovascular, musculoskeletal and cancer biology

“…It was further shown that Inc-CTD2383M3.1 acted as a competing endogenous RNA by competitively binding to miR-210-3p, thus alleviating suppression of ADAMTS6 ( Jiang et al, 2020 ). A further study, utilizing bioinformatics, showed that ADAMTS6 is a potential hub for miRNAs of oral fluids related to orthodontics ( Kapoor et al, 2021 ). Bioinformatics, RNAseq and qRT-PCR analysis, along with in vitro studies, showed that circular (circ) ADAMTS6 RNA, a type of noncoding RNA, was downregulated after treatment of IL-1β ( Fu et al, 2021 ).…”