Noncoding RNAs in periodontitis: Progress and perspectives (Review)

Abstract

Periodontitis is the sixth most common chronic non‑infectious disease in the world. It mainly leads to the inflammatory destruction of periodontal supporting tissue, which has become the main cause of tooth loss in adults. Periodontitis is also a risk factor for various systemic diseases. Noncoding ribonucleic acids (ncRNAs) are important regulators of normal biological processes and their abnormal expression has been shown to be important to the pathogenesis of inflammatory diseases, including periodontitis. Biologically, they can regulate immune inflammation, bone homeostasis and cell proliferation in periodontitis. Clinically, they are promising diagnostic markers and therapeutic targets. Recent advances in technology have opened up new directions for the study of ncRNAs, including RNA secondary structures, RNA protein interactions, ncRNA‑encoded peptides or proteins and single‑cell RNA sequencing. Therefore, the present study summarized the function and mechanisms of ncRNAs in periodontitis, as well as their clinical potential for diagnosis and treatment and highlight these exciting areas of research.

Keywords: circular RNA; long noncoding RNA; noncoding RNA; periodontitis; therapeutics.

Figure 1

Graphical Abstract. Brief overview of ncRNAs in periodontitis. NcRNAs not only regulate immune inflammation, bone homeostasis and cell proliferation in periodontitis, but also serve as diagnostic marker and nucleic acid drug. nc, noncoding; GCF, gingival crevicular fluid.

Figure 2

Brief overview of ncRNAs regulate immune inflammation in periodontitis. LncRNA PTCSC3 can downregulate TLR4 and lncRNA MFG-AS1 was found to upregulate TLR4. LncRNA NEAT1, lncRNA ZFY-AS1, lncRNA MALAT1, Linc01126, Circ_0138959, CircPVT1, Linc00616 and Circ_0099630 are markedly increased in the pathogenesis of periodontitis, which targeting miRNA and upregulating target proteins and then which promoting the occurrence and development of periodontal disease. LncRNA LOXL1-AS1, LncRNA SNHG5, Circ_0003948, Circ_0062491, Circ_0085289 are down-regulated in the pathogenesis of periodontitis and play a protective role in periodontitis. The black arrowheads indicate promotion and the red T indicate inhibition. nc, noncoding; lnc, long noncoding; linc, long intergenic noncoding; circ, circular; mi, micro; TLR4, Toll-like receptor 4; TRAF6, TNF receptor-associated factor 6; Bax, Bcl-2-associated X protein; Bcl-2, B-cell lymphoma 2; DDX3X, DEAD-box helicase 3 X-linked; NF-κB, nuclear factor kappa-B; HIF-1α, hypoxia inducible factor 1 alpha; MAPK, mitogen-activated protein kinase; JAK2, Janus kinase 2; STAT3, signal transducer and activator of transcription 3; NR2F2, nuclear receptor subfamily 2 group F member 2; PTEN, phosphatase and tensin homolog; NRF-2, nuclear factor (erythroid-derived 2)-like 2; HO-1, heme oxygenase-1; TFRC, transferrin receptor; LfR, lactoferrin receptor; SOCS6, suppressor of cytokine signaling 6.

Figure 3

NcRNAs regulate bone homeostasis in periodontitis. LncRNAs and circRNAs promote the osteogenic differentiation of PDLSCs and bone resorption of osteoclasts by adsorbing miRNAs as ceRNAs. The black arrowheads indicate promotion and the red T indicate inhibition. nc, noncoding; lnc, long noncoding; Linc, long intergenic noncoding; circ, circular; PDLSCs, periodontal ligament stem cells; mi, micro; ce, competing endogenous; SMAD6, mothers against decapentaplegic homolog 6; IGF-1R, insulin-like growth factor 1 receptor; HIF-1α, hypoxia inducible factor 1 alpha; MAPK, mitogen-activated protein kinase; HES1, hes family BHLH transcription factor 1; PLAP-1, periodontal-ligament–associated protein-1; ETS1, erythroblast transformation specific 1; FOXO1, forkhead box O1; RO60, Y RNA binding protein; BGLAP, bone gamma-carboxyglutamate protein; FGFR1, fibroblast growth factor receptor 1; IGF1, insulin-like growth factor 1; AKT, protein kinase B; IKK, inhibitor of NF-κB kinase; NF-κB, nuclear factor kappa-B; C/EBP-β, CCAAT-enhancer-binding protein-β; NLRP3, NLR family pyrin domain containing 3; CHRDL1, chordin like 1; BMP7, bone morphogenetic protein 7; SMAD5, mothers against decapentaplegic homolog 5; RUNX2, runt-related transcription factor 2; Zeb2, zinc finger E-box binding homeobox 2; TRAF6, TNF receptor-associated factor 6.

Figure 4

NcRNAs regulate the proliferation of PDLSCs/PDLCs. From left to right of figure shows PDLSCs/PDLCs proliferation. The gray area is the ncRNA that promotes the proliferation of PDLSCs/PDLCs and the yellow area is the ncRNA that inhibits the proliferation of PDLSCs/PDLCs. The black arrowheads indicate promotion and the red T indicate inhibition. Bold red arrowheads indicate the molecules with increased/decreased expression of ncRNA in the process of promoting/inhibiting cell proliferation. nc, noncoding; PDLSCs, periodontal ligament stem cells; PDLCs, periodontal ligament cells; YAP1, yes-associated protein 1; FGF2, fibroblast growth factor 2; TLR4, Toll-like receptor 4; PLAP-1, periodontal-ligament-associated protein-1; CDK4, cyclin-dependent kinase 4; CDK6, cyclin-dependent kinase 6; CCND-1, cyclin D1; SPRY1, sprouty RTK signaling antagonist 1; ERK, extracellular signal-regulated kinase.

Figure 5

ROC curve was used to screen biomarkers for early diagnosis of the disease. Firstly, the predicted ncRNA biomarkers were obtained by RNA-seq or database analysis. ROC curve was used to evaluate the reliability of diagnostic biomarkers. The biomarker can be verified clinically to evaluate its diagnostic efficacy. If the biomarker is reliable, it can be prepared as a drug for disease diagnosis. ROC, receiver operating characteristic; nc, noncoding; RNA-seq, RNA-sequences; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; GCF, gingival crevicular fluid; RT-qPCR, reverse transcription quantitative PCR.

Figure 6

Diagnostic potential of ncRNA in periodontitis. NcRNAs in human tissues or various types of body fluids (including serum and urine) can be used as diagnostic markers for systemic diseases. Similarly, different samples such as serum, saliva and GCF can also be used as sources of ncRNAs, which could be used as potential biomarkers. nc, noncoding; GCF, gingival crevicular fluid.

Figure 7

Therapeutic potential of ncRNAs. (A) Nucleic acid delivery systems deliver ncRNA for the treatment of digestive, respiratory and circulatory system diseases. (B) Animal researches on ncRNA as nucleic acid drugs for disease treatment. (C) The advantages of ncRNA carriers (exosomes, lipid nanoparticles, polymer nanoparticles). nc, noncoding.