Overview of noncoding RNAs involved in the osteogenic differentiation of periodontal ligament stem cells

Table 1 Expression profile of ncRNAs involved in the osteogenic differentiation of periodontal ligament stem cells

ncRNAs	Method	Subjects	Results	Ref.
mi-RNA	Microarray	3 hPDLSCs from normal healthy premolars without periodontitis or caries cultured in mineralized medium and 3 in non-mineralized medium	30 upregulated and 86 downregulated miRNAs (P < 0.05, FC ≥ 2)	Hao et al[37] 2017
mi-RNA	Microarray	6 samples from untreated hPDLSCs and 6 hPDLSCs under osteogenic induction	miR-24-3p with the minimum fold change was significantly downregulated (P < 0.05, FC ≥ 2)	Li et al[38] 2019
mi-RNA	Microarray	3 hPDLSCs cultured with 5.5 mmol/L glucose or 3 cultured with 25 mmol/L glucose mineralized medium	Analyzed 700 miRNAs and found miR-31 was the most upregulated in hPDLSCs cultured with 25 mmol/L glucose (P < 0.01, FC ≥ 2)	Zhen et al[48] 2017
mi-RNA	Microarray	3 hPDLSCs from 3 volunteers not subjected to stretch and 3 hPDLSCs from 3 volunteers subjected to mechanical stretch	26 miRNAs were up-regulated while 27 miRNAs were down-regulated with stretching (P < 0.01, FC ≥ 2)	Wei et al[55] 2014
lncRNA	RNA sequencing	3 PDLSCs every group cultured in an osteogenic medium for 0, 3, 7, or 14 d	lncRNAs showed stage-specific expression, and 17 lncRNAs were up-regulated while31 were down-regulated in PDLSCs in an osteogenic medium for 3, 7, or 14 d (P < 0.05, FC ≥ 2)	Zheng et al[68] 2018
lncRNA	Microarray	3 hPDLSCs both in osteoblast-induced group and non-induced group	994 lncRNAs were up-regulated and 1177 lncRNAs were down-regulated during osteogenic differentiation in PDLSCs at 14 d (P < 0.05, FC ≥ 2)	Qu et al[69] 2016
lncRNA	RNA sequencing	3 hPDLSCs subjected to static compressive stress (2 g/cm2) for 12 h and 3 normal hPDLSCs	72 lncRNAs were upregulated and 18 downregulated by compressive stress (P < 0.05, FC ≥ 1.5)	Huang et al[70] 2019
lncRNA	Microarray	3 noninduced and 3 osteogenically induced hPDLSCs	12 upregulated and 8 downregulated lncRNAs and MEG3 belonging to significant downregulation genes in induced cells (P < 0.05, FC ≥ 2)	Liu et al[73] 2019
lncRNA	Microarray	3 hPDLSCs from 3 normal persons and 3 pPDLSCs from 3 periodontitis patients with osteogenic differentiation	89 lncRNAs were differentially expressed between the two groups of cells and lncRNA-POIR was the most significantly altered between the non-induced group and osteogenic-induced group (P < 0.05, FC > 2)	Wang et al[77] 2016
lncRNA and circRNA	RNA sequencing	3 samples from untreated hPDLSCs and 3 hPDLSCs under osteogenic induction	A total of 960 lncRNAs and 1456 circRNAs were found to be differentially expressed (P < 0.05, FC ≥ 2)	Gu et al[67] 2017
circRNA	RNA sequencing	3 hPDLSCs were subjected to mechanical force and 3 hPDLSCs were not subjected to force	identified 2970 and 2788 circRNAs, respectively, in the control group and the force group, and 1191 circRNAs were significantly upregulated and 1,487 were downregulated in the force group (P < 0.05, FC > 2)	Wang et al[89] 2019

miRNAs: MicroRNAs; lncRNAs: Long non-coding RNAs; circRNAs: Circular RNAs; hPDLSCs: Human periodontal ligament stem cells; PDLSCs: Periodontal ligament stem cells; MEG3: Maternally expressed gene 3; POIR: Osteogenesis impairment-related lncRNA of PDLSCs.

Table 2 Overview of ncRNAs involved in the osteogenic differentiation of periodontal ligament stem cells

ncRNAs	Regulatory levels	Modes of action	Associated signaling pathways or biomarkers	Ref.
miR-24-3p	Posttranscriptional regulation	Interacting with Smad5 3′-UTR	Inhibits Smad5 and Runx2, BMP2, OCN biomarkers	Li et al[38] 2019
miR-21	Posttranscriptional regulation	Interacting with Smad5 3′-UTR	Inhibits Smad5 and Runx2, ALP, BSP, OSX biomarkers	Wei et al[39] 2017
		Interacting with Spry1 3′-UTR	Inhibits Spry1 and Runx2, OSX biomarkers	Yang et al[40] 2017
		Interacting with ACVR2B 3′-UTR	Inhibits ACVR2B and enhances Runx2, OCN, ALP biomarkers	Wei et al[56] 2015
miR-203	Posttranscriptional regulation	Interacting with Runx2 3′-UTR	Inhibits Runx2 and ALP, OCN, OPN biomarkers	Feng et al[41] 2019
miR-1305	Posttranscriptional regulation	Interacting with Runx2 3′-UTR	Inhibits Runx2 and ALP, OCN, OPN biomarkers	Chen et al[42] 2017
miR-218	Posttranscriptional regulation	Interacting with Runx2 3′-UTR	Inhibits Runx2 and OCT4, NANOG cytokines	Gay et al[43] 2014
miR-214	Posttranscriptional regulation	Interacting with ATF4 3′-UTR	Inhibits ATF4 and Runx2, ALP, OCN biomarkers	Yao et al[44] 2017
		Interacting with CTNNB1 3′-UTR	Activates Wnt/β-catenin signaling pathway and inhibits ALP, OCN, BSP biomarkers	Cao et al[45] 2017
miR-17	Posttranscriptional regulation	Interacting with TCF3 3′-UTR	Inhibits Runx2, ALP biomarkers	Liu et al[46] 2013
		Interacting with Smurf1 3′-UTR	Activates Smad family proteins and Runx2, ALP, OCN biomarkers	Liu et al[47] 2011
miR-31	Posttranscriptional regulation	Interacting with Stab2 3′-UTR	Inhibits Stab2 and Runx2, OSX, OCN biomarkers	Zhen et al[48] 2017
miR-200c	Posttranscriptional regulation	Interacting with IL-6, IL-1β and CCL-5 3′-UTRs	Inhibits IL-6, IL-1β, CCL-5 and enhances Runx2, ALP, OCN, OPG biomarkers	Hong et al[49] 2016
miR-543	Posttranscriptional regulation	Interacting with TOB2 3′-UTR	Inhibits TOB2 and enhances Runx2, ALP, BSP, COL1A1 biomarkers	Ge et al[50] 2018
miR-22	Posttranscriptional regulation	Interacting with HDAC6 3′-UTR	Inhibits HDAC6 and enhances Runx2, OCN biomarkers	Yan et al[51] 2017
lncRNA TUG1	Transcriptional regulation	Binding with Lin28A protein	Promotes Lin28A and Runx2, ALP, OCN biomarkers	He et al[72] 2018
lncRNA MEG3	Transcriptional regulation	Suppresses BMP2 through binding with hnRNPI protein	Inhibits BMP2 and Runx2, ALP, OCN biomarkers	Liu et al[73] 2019
lncRNA ANCR	Transcriptional regulation	Activates Wnt/β-catenin signaling pathway indirectly	Activates Wnt/β-catenin signaling pathway and inhibits ALP, BSP, DSPP, OCN, Runx2, Gsk3-β biomarkers	Jia et al[74] 2015
	Posttranscriptional regulation	lncRNA ANCR/miR-758/Notch2 axis “ceRNA”	Activates Notch2-Wnt/β-catenin signaling pathway and inhibits ALP, Runx2, OSX biomarkers	Peng et al[78] 2018
	Epigenetic regulation	Interacting with EZH2 and catalysis H3K27me3 of Runx2	Inhibits Runx2 and ALP, OCN biomarkers	Zhu et al[82] 2013
lncRNA POIR	Posttranscriptional regulation	LncRNA POIR/miR 182/FoxO1 axis “ceRNA”	Inhibits TCF-4-Wnt/β-catenin signaling pathway and promotes ALP, Runx2, COL1 biomarkers	Wang et al[77] 2016
lncRNA PCAT1	Posttranscriptional regulation	A feed-forward regulatory loop of lncPCAT1/miR-106a-5p/E2F5/ BMP2 axis “ceRNA”	Activates BMP2 and ALP, Runx2, OSX biomarkers	Jia et al[79] 2019
lncRNA HIF1A‑AS2	Posttranscriptional regulation	Base complementary pairing with the mRNA of HIF-1α	Inhibits HIF-1α and ALP, Runx2 biomarkers	Chen et al[80] 2017
circRNA CDR1as	Posttranscriptional regulation	circRNA CDR1as /miR-7/GDF5 axis “ceRNA”	Enhances Smad1/5/8 and p38 MAPK phosphorylation and promotes ALP, BMP2, Runx2, OCN biomarkers	Li et al[88] 2018
circRNA3140	Posttranscriptional regulation	CircRNA3140/miR-21/ACVR2B axis “ceRNA”	Promotes ACVR2B and inhibits Runx2, OCN, SP7 biomarkers	Wang et al[89] 2019

miRNAs: MicroRNAs; lncRNAs: Long non-coding RNAs; circRNAs: Circular RNAs; hPDLSCs: Human periodontal ligament stem cells; PDLSCs: Periodontal ligament stem cells; Smad5/: SMAD family member 5; Runx2: Runt-related transcription factor 2; BMP2: Bone morphogenetic protein-2; OCN: Osteocalcin; ALP: Alkaline phosphatase; BSP: Bone Sialoprotein; OSX: Osterix; Spry1: Palmitate phosphoprotein Sprouty1; ACVR2B: Activin A receptor type 2B; OPN: Osteopontin; OCT4: Octamer-binding transcription factor-4; NANOG: Homeobox transcription factor nanog; ATF4: Activated transcription factor 4; CTNNB1: Catenin beta 1; TCF3: Transcriptional factor 3; Smurf1: Smad ubiquitin regulatory factor 1; Satb2: Special AT-rich sequence-binding protein 2; IL: Interleukin; CCL-5: Chemokines-5; OPG: Osteoprotegerin; TOB2: Transducer of ERBB2; COL1A1: Collagen type I alpha 1 chain; HDAC6: Histone deacetylase 6; Lin28A: Lin-28 homolog A; hnRNP I: Heterogeneous nuclear ribonucleoprotein I; DSPP: Dentin sialophosphoprotein; GSK3β: Glycogen synthase kinase 3β; ANCR: Anti-differentiation noncoding RNA; Notch2: Neurogenic locus notch homolog protein 2; ceRNA: Competing endogenous RNAs; EZH2: Enhancer of zeste homolog 2; H3K27me3: Histone H3 trimethylated at lysine 27; POIR: Osteogenesis impairment-related lncRNA of PDLSCs; FoxO1: Forkhead box O1; TCF4: Transcription factor 4; COL1: Collagen type I; PCAT1: Prostate cancer-associated ncRNA transcript-1; HIF1A‑AS1/2: HIF1A antisense RNA 1/2; HIF-1α: Hypoxia-inducible factor-1α; CDR1as: Antisense to the cerebellar degeneration-related protein 1 transcript; GDF5: Growth differentiation factor 5; MAPK: Mitogen-activated protein kinase; ACVR2B: Activin A receptor type 2B; SP7: Transcription Factor Sp7.