Skip to main content

The regulation mechanism of LINC00707 on the osteogenic differentiation of human periodontal ligament stem cells


The osteogenic differentiation of periodontal ligament stem cells (PDLSCs) is important for periodontal tissue repair and regeneration. Long non-coding RNAs (lncRNAs) are key regulators of diverse biological processes. However, their roles in PDLSC osteogenic differentiation are still largely unknown. This study explored the effect of LINC00707 and its mechanism on the osteogenic differentiation of human PDLSCs. Results showed an increase in LINC00707 and forkhead box O1 (FOXO1) but a decrease in miR-490-3p during PDLSC osteogenic differentiation. LINC00707 and FOXO1 promoted osteogenic differentiation as evidenced by the formation of calcium nodules and the increase in osteogenic markers such as alkaline phosphatase, osteocalcin (OCN), and runt-related transcription factor 2 (Runx2). LINC00707 and FOXO1 knockdown exhibited opposite effects. Dual-luciferase reporter assay and qRT-PCR showed that LINC00707 can specially bind to miR-490-3p, which reversed the effect of LINC00707 on PDLSCs. MiR-490-3p inhibitor relieved the inhibiting effect of sh-LINC00707 on osteogenic differentiation. Further investigation revealed that LINC00707 can promote osteogenic differentiation by regulating FOXO1 expression through miR-490-3p sponging. Thus, the LINC00707/miR-490-3p/FOXO1 axis modulated PDLSC osteogenic differentiation and might be a promising therapeutic target for periodontal diseases.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Data availability

All data generated or analysed during this study are included in this published article.


  1. Beermann J, Piccoli MT, Viereck J, Thum T (2016) Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches. Physiol Rev 96:1297–1325

    CAS  Article  Google Scholar 

  2. Chen S, Chen Xi, Xiu YinLing et al (2014) microRNA 490–3P enhances the drug-resistance of human ovarian cancer cells. J Ovarian Res 7:84

    Article  Google Scholar 

  3. Chen DJ, Xiang ML, Gong YY et al (2019) LIPUS promotes FOXO1 accumulation by downregulating miR-182 to enhance osteogenic differentiation in hPDLCs. Biochimie 165:219–228

    CAS  Article  Google Scholar 

  4. Elsa MC, Cátia R, Maria CMC (2018) Chronic periodontitis, inflammatory cytokines, and interrelationship with other chronic diseases. Postgrad Med 130(1):98–104

    Article  Google Scholar 

  5. Ergun S, Oztuzcu S (2015) Oncocers: ceRNA-mediated crosstalk by sponging miRNAs in oncogenic pathways. Tumour Biol 36:3129–36

    CAS  Article  Google Scholar 

  6. Gay IC, Chen S, MacDougall M (2007) Isolation and characterization of multipotent human periodontal ligament stem cells. Orthod Craniofac Res 10(3):149–160

    CAS  Article  Google Scholar 

  7. Han N, Zhang F, Li G, Zhang X, Lin X, Yang H, Wang L, Cao Y, Du J, Fan Z (2017) Local application of IGFBP5 protein enhanced periodontal tissue regeneration via increasing the migration, cell proliferation and osteo/dentinogenic differentiation of mesenchymal stem cells in an inflammatory niche. Stem Cell Res Ther 8:210

    Article  Google Scholar 

  8. He Q, Yang S, Gu X, Li M, Wang C, Wei F (2018) Long noncoding RNA TUG1 facilitates osteogenic differentiation of periodontal ligament stem cells via interacting with Lin28A. Cell Death Dis 9:455

    Article  Google Scholar 

  9. Huang XJ, Chen H, Xie YY et al (2019) FoxO1 overexpression ameliorates TNF-α-induced oxidative damage and promotes osteogenesis of human periodontal ligament stem cells via antioxidant defense activation. Stem Cells Int 2019:2120453

    PubMed  PubMed Central  Google Scholar 

  10. Huang YP, Han YN, Guo RZ et al (2020) Long non-coding RNA FER1L4 promotes osteogenic differentiation of human periodontal ligament stromal cells via miR-874–3p and vascular endothelial growth factor A. Stem Cell Res Ther.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Iyer S, Ambrogini E, Bartell SM, Han L, Roberson PK, de Cabo R et al (2013) FOXOs attenuate bone formation by suppressing Wnt signaling. J Clin Investig 123:3409–3419

    CAS  Article  Google Scholar 

  12. Iyer S, Han L, Ambrogini E, Yavropoulou M, Fowlkes J, Manolagas SC et al (2017) Deletion of Fox O1, 3, and 4 in osteoblast progenitors attenuates the loss of cancellous bone mass in a mouse model of type 1 diabetes. J Bone Miner Res 32:60–69

    CAS  Article  Google Scholar 

  13. Jia B, Qiu X, Chen J, Sun X, Zheng X, Zhao J, Li Q, Wang Z (2019a) A feed-forward regulatory network lncPCAT1/miR-106a-5p/E2F5 regulates the osteogenic differentiation of periodontal ligament stem cells. J Cell Physiol 234(11):19523–19538

    CAS  Article  Google Scholar 

  14. Jia B, Wang ZP, Su X et al (2019b) Long noncoding RNA LINC00707 sponges miR-370-3p to promote osteogenesis of human bone marrow-derived mesenchymal stem cells through upregulating WNT2B. Stem Cell Res Ther 10:67

    CAS  Article  Google Scholar 

  15. Jiang H, Jia PZ (2021) MiR-153-3p inhibits osteogenic differentiation of periodontal ligament stem cells through KDM6A-induced demethylation of H3K27me3. J Periodontal Res 56(2):379–387

    CAS  Article  Google Scholar 

  16. Kang NN, Ge SL, Zhang RQ et al (2018) MiR-490-3p inhibited the proliferation and metastasis of esophageal squamous cell carcinoma by targeting HMGA2. Eur Rev Med Pharmacol Sci 22(23):8298–8305

    PubMed  Google Scholar 

  17. Kousteni S (2011) FoxO1: a molecule for all seasons. J Bone Miner Res 26(5):912–917

    CAS  Article  Google Scholar 

  18. Liu L, Ling J, Wei X, Wu L, Xiao Y (2009) Stem cell regulatory gene expression in human adult dental pulp and periodontal ligament cells undergoing odontogenic/osteogenic difffferentiation. J Endod 35(10):1368–1376

    Article  Google Scholar 

  19. Liu Y, Zeng X, Miao J, Liu C, Wei F, Liu D, Zheng Z, Ting K, Wang C, Guo J (2019) Upregulation of long noncoding RNA MEG3 inhibits the osteogenic differentiation of periodontal ligament cells. J Cell Physiol 234:4617–4626

    CAS  Article  Google Scholar 

  20. Ma T, Ma H, Zou Z, He X, Liu Y, Shuai Y et al (2018) The long intergenic noncoding RNA 00707 promotes lung adenocarcinoma cell proliferation and migration by regulating Cdc42. Cell Physiol Biochem 45:1566–1580

    CAS  Article  Google Scholar 

  21. Menicanin D, Mrozik KM, Wada N (2014) Periodontal-ligament-derived stem cells exhibit the capacity for long-term survival, self-renewal, and regeneration of multiple tissue types in vivo. Stem Cells Dev 23(9):1001–1011

    CAS  Article  Google Scholar 

  22. Nagano T, Fraser P (2011) No-nonsense functions for long noncoding RNAs. Cell 145:178–181

    CAS  Article  Google Scholar 

  23. Nagatomo K, Komaki M, Sekiya I, Sakaguchi Y, Noguchi K, Oda S, Muneta T, Ishikawa I (2006) Stem cell properties of human periodontal ligament cells. J Periodontal Res 41(4):303–310

    CAS  Article  Google Scholar 

  24. Palle H, Jesper R, Anne HP (2010) Periodontitis is one of the most commonly occurring inflammatory diseases. Ugeskr Laeger 172(44):3029–3032

    Google Scholar 

  25. Park J, Jeon SH, Choung P (2011a) Effiffifficacy of periodontal stem cell transplantation in the treatment of advanced periodontitis. Cell Transplant 20(2):271–285

    Article  Google Scholar 

  26. Park JY, Jeon SH, Choung PH (2011b) Efficacy of periodontal stem cell transplantation in the treatment of advanced periodontitis. Cell Transplant 20:271–285

    Article  Google Scholar 

  27. Rached MT, Kode A, Xu L et al (2010) FoxO1 is a positive regulator of bone formation by favoring protein synthesis and resistance to oxidative stress in osteoblasts. Cell Metab 11(2):147–160

    CAS  Article  Google Scholar 

  28. Seo B, Miura M, Gronthos S et al (2004) Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet 364(9429):149–155

    CAS  Article  Google Scholar 

  29. Siqueira MF, Flowers S, Bhattacharya R, Faibish D, Behl Y, Kotton DN et al (2011) FOXO1 modulates osteoblast differentiation. Bone 48:1043–1051

    CAS  Article  Google Scholar 

  30. Tu JF, Zhao ZW, Xu M et al (2019) LINC00707 contributes to hepatocellular carcinoma progression via sponging miR-206 to increase CDK14. J Cell Physiol 234(7):10615–10624

    CAS  Article  Google Scholar 

  31. Wei FL, Yang SY, Guo QY et al (2019) MicroRNA-21 regulates osteogenic diferentiation of periodontal ligament stem cells by targeting Smad5. J Cell Physiol 234(4):4617–4626

    Article  Google Scholar 

  32. Yan GQ, Wang X, Yang F et al (2017) MicroRNA-22 promoted osteogenic differentiation of human periodontal ligament stem cells by targeting HDAC6. J Cell Biochem 118(7):1653–1658

    CAS  Article  Google Scholar 

  33. Yang X, Qu X, Meng X et al (2018) MiR-490-3p inhibits osteogenic differentiation in thoracic ligamentum flavum cells by targeting FOXO1. Int J Biol Sci 14(11):1457–1465

    CAS  Article  Google Scholar 

  34. Yao SQ, Zhao W, Ou QM et al (2017) MicroRNA-214 suppresses osteogenic differentiation of human periodontal ligament stem cells by targeting ATF4. Stem Cells Int 2017:3028647

    Article  Google Scholar 

  35. Zhu L, Xu PC (2013) Downregulated LncRNA-ANCR promotes osteoblast differentiation by targeting EZH2 and regulating Runx2 expression. Biochem Biophys Res Commun 432:612–617

    CAS  Article  Google Scholar 

Download references


This work was supported by the Fujian Provincial Natural Science Foundation [Grant Number 2020J01646], Young Teacher Education and Research fund of Fujian Provincial Education Department [Grant Number JT180208], People’s Republic of China.

Author information



Corresponding author

Correspondence to Minqian Zheng.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

hPDLSCs were obtained from pre-molars extracted from teenagers whose parents gave informed consent and were approved by the Ethics Committee of The Affiliated Stomatological Hospital of Fujian Medical University (20190027).

Consent to participate

All patients signed written informed consent forms.

Consent for publication

Written informed consent for publication was obtained from all participants.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.


Supplementary file1 Imaging of PDLSCs cultured in normal media after the third passage (P3) by optical microscopy (JPG 2237 kb)


Supplementary file2 Identification of the mesenchymal stem cell surface markers of PDLSCs by flow cytometry. All experiments were performed in triplicate, and results were expressed as means ± SD (TIF 16441 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Guo, J., Zheng, M. The regulation mechanism of LINC00707 on the osteogenic differentiation of human periodontal ligament stem cells. J Mol Histol (2021).

Download citation


  • PDLSCs
  • Osteogenic differentiation
  • LINC00707
  • miR-490-3p
  • FOXO1