School of Dental Sciences, Sharda University, Greater Noida, UP, India.
Department of Orthodontics, Faculty of Dentistry, Jamia Millia Islamia, New Delhi, 110025, India.
Prog Orthod. 2021 Oct 11;22(1):31. doi: 10.1186/s40510-021-00377-1.
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.
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.
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.
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.
微小 RNA（miRNAs）是一类非编码的短链单链 RNA 分子，可能作为正畸力应用后骨和组织重塑的各种炎症和分子机制的生物标志物。
2021 年 3 月，我们通过严格的 PRISMA 选择标准对主要数据库进行了全面的文献检索，以生成正畸学中 miRNAs 的证据。最初的搜索发现了 920 篇文章，随后根据 PRISMA 进行了严格的选择标准筛选，最终纳入了四项研究。QUADAS-2 质量评估将三项研究归类为不确定风险偏倚，而适用性较高。此外，还进行了生物信息学分析，以从 miRNA 数据库（miRDB）和 TargetScan 数据库中识别靶基因，并使用 STRING 分析识别其蛋白-蛋白相互作用途径。
在正畸患者的龈沟液（GCF）中观察到多种 miRNA，包括 miRNA-21、27(a/b)、29(a/b/c)、34、146(a/b)、101 和 214 以及基质金属蛋白酶（MMPs）-1、2、3、8、9、14。一项研究发现，miRNA-29a/b/c、101、21 的表达在治疗前（开始回缩前）呈统计学显著增加，在回缩的 4-6 周（wk）达到峰值。相反，miRNA-34a 的表达从回缩的第 1 天到 4 周下降，并且与同一观察时间的 MMPs-2、9、14 水平呈负相关。犬牙移动的距离与回缩 2 周时的 miRNA-27a/b、214 呈轻度相关。生物信息学分析揭示了 1213 个相互作用的靶基因，并用 Cytoscape 插件 MCODE 分析它们之间的关系途径。此外，从 STRING 数据库中还确定了 894 个显著的蛋白质相互作用，并从 STRING 数据库中识别出 SMAD4、IGF1、ADAMTS6、COL4A1、COL1A1、COL3A1、FGFR1、COL19A1、FBN1、COL5A1、MGAT4A、LTBP1、MSR1、COL11A1 和 COL5A3 作为枢纽基因。它们的相互作用能够分离多种 miRNA：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，这些 miRNA 有望成为牙齿移动的生物标志物。
我们的结果支持将 miRNAs 用作各种正畸研究设计中的生物标志物，并支持其与牙周病、癌前病变或肥胖或代谢异常等病理状态的相互关系。鉴定的靶基因及其蛋白相互作用途径可用于提出精准治疗方案，重点关注理想的牙齿移动，尽量减少医源性副作用。
