Skip to main content

Advertisement

SpringerLink
Log in

Association of high HIF-1α levels in serous periodontitis with external root resorption by the NFATc1 pathway

  • Original Paper
  • Published:
Journal of Molecular Histology Aims and scope Submit manuscript

Abstract

Whether external root resorption is associated with hypoxia in the periodontal ligaments of teeth with severe periodontitis remains unclear. Hypoxia inducible factor-1α (HIF-1α) expression and external resorption sites in the periodontal ligaments of these teeth were observed to elaborate upon the relationship between hypoxia and external root resorption in severe periodontitis. Histological analysis was performed to observe external root resorption. The expressions of HIF-1α and Nuclear factor-activated T cells c1 (NFATc1) in the periodontal ligaments were detected by immunofluorescence, western blotting and real-time PCR. Bone marrow macrophages (BMMs) were stimulated by Porphyromonas gingivalis lipopolysaccharide (Pg.LPS) and cultured under hypoxia in vitro. High levels of HIF-1α and NFATc1 were detected in severe periodontitis. HIF-1α positive-cells were observed in the external resorption sites. Hypoxia promoted Pg.LPS-stimulated osteoclastogenesis of BMMs and bone resorption by the NFATc1 pathway. Increased HIF-1α in severe periodontitis are associated with external root resorption by the NFATc1 pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  • Abbott PV (2016) Prevention and management of external inflammatory resorption following trauma to teeth. Aust Dent J 61(Suppl 1):82–94

    Article  Google Scholar 

  • Arnett TR, Gibbons DC, Utting JC, Orriss IR, Hoebertz A, Rosendaal M et al (2003) Hypoxia is a major stimulator of osteoclast formation and bone resorption. J Cell Physiol 196(1):2–8

    Article  CAS  Google Scholar 

  • Blouin CC, Page EL, Soucy GM, Richard DE (2004) Hypoxic gene activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor 1alpha. Blood 103(3):1124–1130

    Article  CAS  Google Scholar 

  • Chen LL, Yan J (2001) Porphyromonas gingivalis lipopolysaccharide activated bone resorption of osteoclasts by inducing IL-1, TNF, and PGE. Acta Pharmacol Sin 22(7):614–618

    CAS  PubMed  Google Scholar 

  • Chen X, Chen X, Zhou Z, Mao Y, Wang Y, Ma Z et al (2019a) Nirogacestat suppresses RANKL-Induced osteoclast formation in vitro and attenuates LPS-Induced bone resorption in vivo. Exp Cell Res 382(1):111470

    Article  CAS  Google Scholar 

  • Chen X, Chen X, Zhou Z, Qin A, Wang Y, Fan B (2019) LY411575, a potent gamma-secretase inhibitor, suppresses osteoclastogenesis in vitro and LPS-induced calvarial osteolysis in vivo. J Cell Physiol 234(11):20944–20956

    Article  CAS  Google Scholar 

  • Chen X, Yu X, Yan K, Liu S, Sun Z, Li S (2020) Multiple idiopathic cervical root resorption involving all permanent teeth. Aust Endod J. https://doi.org/10.1111/aej.12398

    Article  PubMed  Google Scholar 

  • Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N et al (2003) HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112(5):645–657

    Article  CAS  Google Scholar 

  • Gölz L, Memmert S, Rath-Deschner B, Jäger A, Appel T, Baumgarten G et al (2015a) Hypoxia and P. gingivalis synergistically induce HIF-1 and NF-κB activation in PDL cells and periodontal diseases. Mediat Inflamm 2015:438085

    Article  Google Scholar 

  • Gölz L, Memmert S, Rath-Deschner B, Jäger A, Appel T, Baumgarten G et al (2015b) Hypoxia and P. gingivalis synergistically induce HIF-1 and NF-κB activation in PDL cells and periodontal diseases. Mediat Inflamm 2015:438085–438085

    Article  Google Scholar 

  • Iglesias-Linares A, Hartsfield JK Jr (2017) Cellular and molecular pathways leading to external root resorption. J Dent Res 96(2):145–152

    Article  CAS  Google Scholar 

  • Ikeda F, Nishimura R, Matsubara T, Tanaka S, Inoue J, Reddy SV et al (2004) Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation. J Clin Invest 114(4):475–484

    Article  CAS  Google Scholar 

  • Kato H, Taguchi Y, Tominaga K, Umeda M, Tanaka A (2014) Porphyromonas gingivalis LPS inhibits osteoblastic differentiation and promotes pro-inflammatory cytokine production in human periodontal ligament stem cells. Arch Oral Biol 59(2):167–175

    Article  CAS  Google Scholar 

  • Knowles HJ, Cleton-Jansen AM, Korsching E, Athanasou NA (2010) Hypoxia-inducible factor regulates osteoclast-mediated bone resorption: role of angiopoietin-like 4. FASEB J 24(12):4648–4659

    CAS  PubMed  PubMed Central  Google Scholar 

  • Knowles HJ (2017) Hypoxia-induced fibroblast growth factor 11 stimulates osteoclast-mediated resorption of bone. Calcif Tissue Int 100(4):382–391

    Article  CAS  Google Scholar 

  • Liu F, Wang Y, Xu J, Liu F, Hu R, Deng H (2016) Effects of Porphyromonas gingivalis lipopolysaccharide on the expression of key genes involved in cholesterol metabolism in macrophages. Arch Med Sci AMS 12(5):959–967

    Article  CAS  Google Scholar 

  • Ma Z, Yu R, Zhao J, Sun L, Jian L, Li C et al (2019) Constant hypoxia inhibits osteoclast differentiation and bone resorption by regulating phosphorylation of JNK and IκBα. Inflamm Res 68(2):157–166

    Article  CAS  Google Scholar 

  • Mavridou AM, Hilkens P, Lambrichts I, Hauben E, Wevers M, Bergmans L et al (2019) Is hypoxia related to external cervical resorption? A case report. J Endod 45(4):459–470

    Article  Google Scholar 

  • Muzylak M, Price JS, Horton MA (2006) Hypoxia induces giant osteoclast formation and extensive bone resorption in the cat. Calcif Tissue Int 79(5):301–309

    Article  CAS  Google Scholar 

  • Patel S, Foschi F, Mannocci F, Patel K (2018) External cervical resorption: a three-dimensional classification. Int Endod J 51(2):206–214

    Article  CAS  Google Scholar 

  • Pereira SA, Melo A, Resende E, Regateiro F, Coimbra Silva H (2018) Antagonistic effect of IL1 variants in periodontitis and external apical root resorption: evidence from a literature review. Arch Oral Biol 95:195–201

    Article  CAS  Google Scholar 

  • Popescu SM, Mercu TV, Scrieciu M, Mercu TR, Popescu FD, Chiriac AM et al (2017) Radiological and optical coherence tomography aspects in external root resorption. Rom J Morphol Embryol 58(1):131–137

    PubMed  Google Scholar 

  • Russo R, Mallia S, Zito F, Lampiasi N (2019) Gene expression profiling of NFATc1-knockdown in RAW 264.7 cells: an alternative pathway for macrophage differentiation. Cells 8(2):131

    Article  CAS  Google Scholar 

  • Semenza GL (2014) Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol 9:47–71

    Article  CAS  Google Scholar 

  • Song MK, Park C, Lee YD, Kim H, Kim MK, Kwon JO et al (2018) Galpha12 regulates osteoclastogenesis by modulating NFATc1 expression. J Cell Mol Med Sci 22(2):849–860

    CAS  Google Scholar 

  • Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H et al (2002) Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 3(6):889–901

    Article  CAS  Google Scholar 

  • Takedachi M, Iyama M, Sawada K, Mori K, Yamamoto S, Morimoto C et al (2017) Hypoxia-inducible factor-1alpha inhibits interleukin-6 and -8 production in gingival epithelial cells during hypoxia. J Periodontal Res 52(1):127–134

    Article  CAS  Google Scholar 

  • Wang Y, Chen X, Chen X, Zhou Z, Xu W (2019) AZD8835 inhibits osteoclastogenesis and periodontitis-induced alveolar bone loss in rats. J Cell Physiol 234(7):10432–10444

    Article  CAS  Google Scholar 

  • Wu JY, Li X, Wang CL, Ye L, Yang J (2019) Research progress on the pathogenesis of inflammatory external root resorption. Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China J Stomatol 37(6):656–659.

  • Xue L, Su L, Zhao L, Li J, Du Y, Yu X (2018) Cyclophilin a increases CD68(+) cell infiltration in rat experimental periodontitis. J Mol Histol 49(2):157–164

    Article  CAS  Google Scholar 

  • Yan B, Zhang H, Dai T, Gu Y, Qiu X, Hu C et al (2018) Necrostatin-1 promotes ectopic periodontal tissue like structure regeneration in LPS-treated PDLSCs. PLoS ONE 13(11):e0207760

    Article  Google Scholar 

  • Yu X, Gong Z, Lin Q, Wang W, Liu S, Li S (2017) Denervation effectively aggravates rat experimental periodontitis. J Periodontal Res 52(6):1011–1020

    Article  CAS  Google Scholar 

  • Yu XJ, Xiao CJ, Du YM, Liu S, Du Y, Li S (2015) Effect of hypoxia on the expression of RANKL/OPG in human periodontal ligament cells in vitro. Int J Clin Exp Pathol 8(10):12929–12935

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao C, Chen Q, Yu S, Xu C, Li X, Zhang C et al (2020) Effect of interleukin-22 on osteogenic differentiation and the osteoclastogenic response of human periodontal ligament fibroblasts in vitro. J Periodontol. https://doi.org/10.1002/JPER.19-0470

    Article  PubMed  Google Scholar 

  • Zhu J, Tang Y, Wu Q, Ji YC, Kang FW (2019). [Mechanism of participation of osteocytes in the formation of osteoclasts under hypoxia]. Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology 37(5):463–468.

Download references

Acknowledgements

Clinical Medicine Science and Technology Innovation Plan of Jinan (201907099).

Author information

Author notes

  1. Changjie Xiao and Guangliang Bai have contributed equally to this work.

Authors and Affiliations

  1. Department of Endodontics, Jinan Stomatological Hospital, Jinan, Shandong, People’s Republic of China

    Changjie Xiao, Yanmei Du, Huan Jiang & Xijiao Yu

  2. Department of Oral Medicine, Liaocheng Peoples Hospital, Liaocheng, Shandong, People’s Republic of China

    Guangliang Bai

Authors
  1. Changjie Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guangliang Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yanmei Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huan Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xijiao Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Huan Jiang or Xijiao Yu.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xiao, C., Bai, G., Du, Y. et al. Association of high HIF-1α levels in serous periodontitis with external root resorption by the NFATc1 pathway. J Mol Hist 51, 649–658 (2020). https://doi.org/10.1007/s10735-020-09911-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10735-020-09911-7

Keywords

Search

Navigation