1. Periodontal Disease and Regeneration
2. circRNA Biogenesis and Function
2.1. What Are circRNAs?
2.2. The Characterisation and Function of circRNAs
2.3. Methods for Detecting circRNA
3. circRNA Expression in Periodontal Tissues
4. The Emerging Role of circRNAs in Periodontal Regeneration
4.1. Periodontal Tissue Engineering
4.2. The Role of circRNA in Human Periodontal Ligament Stem Cell Differentiation
4.3. The Impact of circRNAs in the Differentiation of Human Dental Pulp Stem Cells (hDPSCs)
4.4. circRNAs in MC3T3-E1, Rat Dental Follicle Cells (rDFCs), and Gingival Fibroblasts
5. Conclusions and Future Directions
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
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|Reference||circRNA Name (Gene Name), Genome Location and Length||circRNA Target or Pathway||CircRNA |
|Cell (Tissue) Details||Key Findings|
|Yu et al. 2021 ||circMAP3K11 (MAP3K11)||miR-511||RT-qPCR10||PDL tissues from 10 healthy and 20 periodontitis cases.|
hPDLSCs from healthy donors.
|Higher expression levels of circMAP3K11 and TLR4, and lower expression levels of miR-511-3p were found in periodontitis affected PDL tissues, compared to healthy controls.|
circMAP3K11 enhanced hPDLSCs proliferation, migration and osteogenic differentiation, and reduced the apoptosis of hPDLSCs in vitro through a circMAP3K11/ miR-511-3p/TLR4 axis.
In vivo—silencing circMAP3K11 can prevent periodontitis development in mice, with decreased cell proliferation and increased apoptosis.
|Zheng et al. 2021. ||hsa_circ_0003489 (circCDK8) chr13:26974589-26975761; 1172 bp||mTOR signalling pathway||RT-qPCR||PDL tissues from 6 healthy and 6 mild/moderate chronic periodontitis patients |
hPDLSCs; Healthy PDL tissues (third molars);
Passage 3 to 5.
CircCDK8 and HIF-1α were increased in PDL tissues from periodontitis patients.|
Overexpression of CircCDK8 decreased osteogenic differentiation of hPDLSCs through the mTOR pathway under hypoxia.
|Wang et al. 2019. ||hsa_circ_0001946; CDR1as (or CiRS-7)|
chrX:139865339-139866824; 1485 bp
ERK/MAPK signal pathway
|RT-qPCR||PDL tissue from 10 periodontitis and 11 healthy cases.|
hPDLSCs from healthy teeth and chronic periodontitis tissue; passage 3.
Donor age 30–40 yrs.
|circCDR1as was significantly downregulated in PDL tissues from periodontitis patients.|
circRNA CDR1as inhibited hPDLSCs proliferation through the miR-7 and ERK/MAPK pathway
|Wang et al. 2021. ||circ_0081572|
chr8:102564942-102571040; 6098 bp
|miR-378h||RT-qPCR||Gingival tissues from 21 healthy and 21 periodontitis cases,|
Human periodontal ligament cells (hPDLCs).
Unclear donor age and cell passage number.
|Circ_0081572 was downregulated in the gingival tissues of periodontitis, compared to healthy gingival tissues.|
Overexpression of circ_0081572 could alleviate LPS-induced PDLCs injury via circ_0081572/miR-378h/RORA axis.
|Li et al. 2019. ||hsa_circ_0062491 |
chr22:23063339-23180200; 116861 bp
|Gingival tissues from 4 healthy and 4 chronic periodontitis cases.|
THP1 cells treated with P. gingivalis.
|1, 304 circRNAs were significantly differentially expressed in the gingival tissues of periodontitis patients (n = 4).|
Decreased circ_0062491 and increased circ_0095812 found in periodontitis-gingival tissues compared to healthy tissues (n = 30) using RT-qPCR.
Circ_0062491 function as a miR-584 sponge in THP1 cells.
|Reference||circRNA Name (Gene Name), Genome Location and Length||circRNA Target or Pathway||CircRNA Detection Method||Cell (Tissue) Details||Key Findings|
|Xie et al. 2021. ||hsa_circ_0087960 (LPAR1) chr9:113734352-113735838; 1486 bp|
hsa_circ_0000437 (CORO1C) chr12:109046047-109048186; 2139 bp
hsa_circ_0000448 (GCN1L1) chr12:120592773-120593523; 750 bp
TGF/β, MAPK, mTOR, and FOXO1 pathways
|Human Periodontal Ligament Stem Cells (hPDLSCs) from third molar tissue; |
Donor ages 18–30 yrs;
|69–557 exosomal circRNAs were detected after 5 and 7 days of osteogenic differentiation of hPDLSCs. |
Exosomal circRNA-LPAR1 was increased and has_circ_0000448 was decreased in hPDLSCs after 5 and 7-days osteogenesis.
Function as miRNA sponge and modulate TGF- β, MAPK, mTOR, and FOXO1 pathways.
|Wang et al. 2018. ||CircRNA3140 |
|hPDLSCs; Middle third root;|
Healthy PDL cells culture;
age 14–16 passage 3
|1191 cricrRNAs in hPDLSC were enhanced by mechanical force-induced osteogenic differentiation.|
Potential functions of circRNAs through circRNAs–miRNAs networks. For instance, circRNA3140 targets miR-21; circRNA436 targets miRNA-107 and miRNA-335.
|Li et al. 2018. ||CDR1as|
hsa_circ_0001946; chrX:139865339-139866824; 1485 bp
TGF-β/Smad and MAPK pathway
PDL tissue from healthy premolars;
|CircRNA CDR1as inhibits osteogenic differentiation of hPDLSCs via inhibiting miR-7, TGF-β/Smad and MAPK pathways; |
In vivo knockdown of CDR1as reduced bone formation in a mouse calvarial defect model.
|Zheng et al. 2017. ||CircCRKL,|
|hPDLSCs (n = 3)|
PDL tissue from a healthy premolar;
Donor age: 12–18;
|12,693 circRNA transcripts were detected in hPDCSc osteogenic differentiation with a time-specific expression.|
Four circRNAs were increased in hPDLSCs osteogenesis by RNA-seq and RT-qPCR;
circRNA-miRNA-mRNA network is the potential regulatory role of circRNA.
|Gu et al. 2017. ||Upregulated: CDR1as, circNCOA3 and circSKIL;|
Downregulated: circIFF01, circNTNG1, circPLOD2, circSMO and circSMURF2
|miRNA34a and miRNA146a;|
MAPK and Wnt pathway
|1456 circRNAs were differentially expressed after 7-day osteogenic differentiated hPDLSCs.|
CDR1as, circNCOA3 and circSKIL upregulated during osteogenesis of hPDLSCs;
CircRNA-miRNA-mRNA network is the potential function of circRNA in hPDLSCs osteogenic differentiation. For instance, circRNA BANP and circRNA ITCH were predicted to interact with miRNA34a and miRNA146a to regulate PDLSC osteogenic differentiation via the MAPK pathway.
|Reference||circRNA Name (Gene Name), Genome Location and Length||circRN |
Target or Pathway
|CircRNA Detection Method||Cell (Tissue) Details||Key Findings|
|Ji et al. 2020. ||circRNA124534/ hsa_circ_0124534|
(FRMD4B) chr3:69247848-69265490; 17,642 bp
|As a miRNA sponge;|
healthy pulp tissues (3 male, 3 female);
Donor age: females: 22–33; males: 26–41
|CircRNA124534 enhanced in vitro osteogenic differentiation in hDPSCs via the miR-496/β-catenin pathway. Over-expression of circRNA124534 in vivo increased bone formation in a mouse subcutaneous model.|
|Chen et al. 2020. ||hsa_circRNA_104101||Wnt and the TGF-β signalling pathway||RT-qPCR|
donor age: 18–25 yrs;
|43 upregulated and 144 downregulated circRNAs were detected in hDPSCs during odontogenic differentiation.|
hsa_circRNA_104101 promoted hDPSCs odontogenic differentiation.
|Ji et al. 2020. ||hsa_circ_0026827|
(RPL41); chr12:56510373-56511616; 1243 bp
Beclin1& RUNX1 pathway
|hDPSCs||has_circ_0026827 was upregulated during osteogenic differentiation in hDPSCs.|
has_circ_0026827 targets the miR-188-3p via Beclin1 & RUNX1 pathway.
Overexpression of has_circ_0026827 promoted in vivo bone formation.
circRNA–miRNA–mRNA networks may operate during odontogenic differentiation in hDPSCs via the Wnt and TGF-β signalling pathways.
|Xie et al. 2020. ||circLPAR1 (hsa_circ_0003611)|
chr9:113703700-113735838; 32,138 bp
SATB2 and RUNX2
|hDPSCs (Exosomes) from one healthy donor (age: 20 yrs);|
|Exosomal crcLPAR1 enhanced osteogenic differentiation of hDPSCs by binding to has-miR-31.|
|Ge et al. 2020. ||circSIPA1L1||miR-617|
Third molar from a healthy donor aged 18–25 yrs;
Passage is unclear
|CircSIPA1L1 promoted osteogenesis via regulating the miR-617 and Smad3 pathway in hDPSCs.|
|Zhang et al. 2020. ||circAKT3 (hsa_circ_0000199) chr1:243708811-243736350; 27,539 bp||miR-206;|
premolars and third molars;
passages 3 to 5
|29 circRNAs were down-regulated and 57 circRNAs were upregulated during hDPSCs osteogenesis. CircAKT3 promoted osteogenesis in hDPSCs by binding to miR-206. |
In vivo—silencing circAKT3 inhibited bone formation in a mouse subcutaneous model.
|Li et al. 2019. ||hsa_circ_0015260 (C1orf9), chr1:172520652-172548407; 27,755 bp|
hsa_circ_0006984 (ZNF79) chr9:130206308-130207528; 1220 bp
|Human dental pulp cells (hDPCs) from healthy premolars and third molars (3 males and 5 females; 12–25 yrs); Passage 3||1341 increased circRNAs and 1780 decreased circRNAs were identified in hDPCs during odontogenic differentiation.|
Has_circ_0015260 and has_circ_0006984 were up-regulated during osteogenesis of hDPCs via miR-135b and the MAPK pathway.
|Reference||circRNA Name (Gene Name), Genome Location and Length||circRNA Target or Pathway||CircRNA Detection Method||Cell (Tissue) Details||Key Findings|
|Cao et al. 2021. ||circ_014154||miR-145a-5p and let-7a-5p;|
|MC3T3-E1||232 upregulated and 95 down-regulated circRNAs were found during osteogenic differentiation of MC3T3-E1 cells under microgravity; Circ_014154 was upregulated in MC3T3-E1 cells with osteogenic differentiation induced by microgravity via miR-145a-5p, let-7a-5p and the MAPK pathway.|
|Wu et al. 2020. ||mmu_circ_003795||mmu‑miR‑1249‑5p|
|MC3T3‑E1 and MDPC23 cells;|
24–72 h after transfection
|mmu_circ_003795 was increased after 72 h osteogensis in MC3T3-E1 and MDPC23 cells by RT-qPCR via mmu‑miR‑ 1249‑5p by targeting COL 15A1.|
|Cao et al. 2020. ||circ-Rtn4||miR-146a||RT-qPCR|
Luciferase reporter assay
|exosomes from circRtn4-modified BMSCs |
|circRtn4 as miR-146a sponge to regulate exosomes from BMSCs reduced TNF-α induced cytotoxicity and inhibited apoptosis of MC3T3-E1.|
Luciferase reporter assay validated the binding between circRtn4 and mi-146a.
|Mi et al. 2019. ||CircRNA AFF4|
Mmu_circ_0000262 chr11:53182161-53194174; 12,013 bp
|MC3T3-E1||In vitro—CircRNA AFF4 stimulated MC3T3-E1 proliferation and inhibited apoptosis via binding to miR-7223-5p, and its downstream target is PIK3R1.|
In vivo—circRNA AFF4 enhanced fracture healing in a mouse femur fracture model.
|Du et al. 2019. ||circFgfr2||miR-133 and BMP6 (bone morphogenetic protein-6);|
|Rat dental |
follicle cells (rDFCs) and tissues;
passage 3 to 4.
|CircFgfr2 promotes osteogenic differentiation of rDFCs via miR-133/BMP6.|
In situ hybridization identified that circFgfr2 was upregulated in mandible dental follicle tissues at days 1 to 11 postnatally in Sprague-Dawley rats, while miR-133 was decreased.
|Yang et al. 2017. ||circ-Amotl1||miR-17-5p|
Stat3, Dnmt3a and fibronectin
|RT-qPCR||Human gingival fibroblast cell line CRL-2014; NIH 3T3 fibroblast cell line.||Circular-Amolt promoted in vivo skin wound healing. Circular-Amolt enhanced hGFs and NIH 3T3 cell migration; Circular-Amolt enhanced STAT3, Dnmt3a and fibronectin while suppressing the expression of miR-17-5p.|
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