Effect of microRNA‑21 on hypoxia‑inducible factor‑1α in orthodontic tooth movement and human periodontal ligament cells under hypoxia

Zhang,Xueqin; Chen,Dongru; Zheng,Jinxuan; Deng,Lidi; Chen,Zhengyuan; Ling,Junqi; Wu,Liping

doi:10.3892/etm.2019.7248

Effect of microRNA‑21 on hypoxia‑inducible factor‑1α in orthodontic tooth movement and human periodontal ligament cells under hypoxia

Authors:
- Xueqin Zhang
- Dongru Chen
- Jinxuan Zheng
- Lidi Deng
- Zhengyuan Chen
- Junqi Ling
- Liping Wu
View Affiliations

Affiliations: Department of Orthodontics, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China, Department of Endodontics, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat‑sen University, Guangzhou, Guangdong 510055, P.R. China
Published online on: February 7, 2019 https://doi.org/10.3892/etm.2019.7248
Pages: 2830-2836

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Orthodontic tooth movement can lead to temporary hypoxia of periodontal tissues. Periodontal ligament cells (PDLCs) react to hypoxia, releasing various biological factors to promote periodontal tissue reconstruction. Hypoxia‑inducible factor‑1α (HIF‑1α) is one of the most sensitive factors involved in the response to hypoxia. HIF‑1α has been identified to be involved in osteogenic and osteoclast differentiation in vitro; however, few studies have investigated the expression of HIF‑1α in the periodontal ligament (PDL) during orthodontic movement in vivo. In a previous study, microRNA‑21 (miR‑21) was demonstrated to be highly expressed in a rat model of orthodontic tooth movement. Additionally, miR‑21 can increase the expression of HIF‑1α in certain tumor cell types and is involved in tumor bioactivities. In the present study, HIF‑1α exhibited expression patterns in a similar way to miR‑21 in PDL samples from a rat model of orthodontic tooth movement, with expression initially increased and followed by a decrease over time. Furthermore, human PDLCs were exposed to a hypoxic environment in vitro, which induced significant upregulation of HIF‑1α and miR‑21 expression. Furthermore, miR‑21 mimics increased HIF‑1α expression and promoted osteogenic differentiation, indicated by upregulated expression of the osteogenic markers osteopontin, runt‑related gene‑2 and alkaline phosphatase. miR‑21 inhibitors suppressed HIF‑1α expression and downregulated the osteogenic markers. In conclusion, the results revealed that miR‑21 has a positive effect on HIF‑1α expression in PDLCs under hypoxia and has important roles in osteogenic differentiation during orthodontic tooth movement. These findings provide a theoretical basis by which to promote tissue reconstruction during orthodontic tooth movement.

View Figures

View References

1	Huang H, Williams RC and Kyrkanides S: Accelerated orthodontic tooth movement: Molecular mechanisms. Am J Orthod Dentofacial Orthop. 146:620–632. 2014. View Article : Google Scholar : PubMed/NCBI
2	de Jong T, Bakker AD, Everts V and Smit TH: The intricate anatomy of the periodontal ligament and its development: Lessons for periodontal regeneration. J Periodont Res. 52:965–974. 2017. View Article : Google Scholar : PubMed/NCBI
3	Niklas A, Proff P, Gosau M and Römer P: The role of hypoxia in orthodontic tooth movement. Int J Dent. 2013:8418402013. View Article : Google Scholar : PubMed/NCBI
4	Nallamshetty S, Chan SY and Loscalzo J: Hypoxia: A master regulator of microRNA biogenesis and activity. Free Radical Biol Med. 64:20–30. 2013. View Article : Google Scholar
5	Mingyuan X, Qianqian P, Shengquan X, Chenyi Y, Rui L, Yichen S and Jinghong X: Hypoxia-inducible factor-1α activates transforming growth factor-β1/Smad signaling and increases collagen deposition in dermal fibroblasts. Oncotarget. 9:3188–3197. 2017.PubMed/NCBI
6	Riddle RC, Khatri R, Schipani E and Clemens TL: Role of hypoxia-inducible factor-1α in angiogenic-osteogenic coupling. J Mol Med (Berl). 87:583–590. 2009. View Article : Google Scholar : PubMed/NCBI
7	Lampert FM, Kütscher C, Stark GB and Finkenzeller G: Overexpression of Hif-1α in mesenchymal stem cells affects cell-autonomous angiogenic and osteogenic parameters. J Cell Biochem. 117:760–768. 2016. View Article : Google Scholar : PubMed/NCBI
8	Chen D, Wu L, Liu L, Gong Q, Zheng J, Peng C and Deng J: Comparison of HIF1A-AS1 and HIF1A-AS2 in regulating HIF-1α and the osteogenic differentiation of PDLCs under hypoxia. Int J Mol Med. 40:1529–1536. 2017. View Article : Google Scholar : PubMed/NCBI
9	Hulley PA, Bishop T, Vernet A, Schneider JE, Edwards JR, Athanasou NA and Knowles HJ: Hypoxia-inducible factor 1-alpha does not regulate osteoclastogenesis but enhances bone resorption activity via prolyl-4-hydroxylase 2. J Pathol. 242:322–333. 2017. View Article : Google Scholar : PubMed/NCBI
10	Lian JB, Stein GS, van Wijnen AJ, Stein JL, Hassan MQ, Gaur T and Zhang Y: MicroRNA control of bone formation and homeostasis. Nat Rev Endocrinol. 8:212–227. 2012. View Article : Google Scholar : PubMed/NCBI
11	Gorospe M, Tominaga K, Wu X, Fähling M and Ivan M: Post-transcriptional control of the hypoxic response by RNA-binding proteins and MicroRNAs. Front Mol Neurosci. 4:72011. View Article : Google Scholar : PubMed/NCBI
12	Mei Y, Bian C, Li J, Du Z, Zhou H, Yang Z and Zhao RCH: miR-21 modulates the ERK-MAPK signaling pathway by regulating SPRY2 expression during human mesenchymal stem cell differentiation. J Cell Biochem. 114:1374–1384. 2013. View Article : Google Scholar : PubMed/NCBI
13	Yang N, Wang G, Hu C, Shi Y, Liao L, Shi S, Cai Y, Cheng S, Wang X, Liu Y, et al: Tumor necrosis factor α suppresses the mesenchymal stem cell osteogenesis promoter miR-21 in estrogen deficiency-induced osteoporosis. J Bone Miner Res. 28:559–573. 2013. View Article : Google Scholar : PubMed/NCBI
14	Liu LZ, Li CY, Chen Q, Jing Y, Carpenter R, Jiang Y, Kung HF, Lai LH and Jiang BH: MiR-21 induced angiogenesis through AKT and ERK activation and HIF-1a expression. PLoS One. 6:e191392011. View Article : Google Scholar : PubMed/NCBI
15	Jiang S, Wang R, Yan H, Jin L, Dou X and Chen D: MicroRNA-21 modulates radiation resistance through upregulation of hypoxia-inducible factor-1alpha-promoted glycolysis in non-small cell lung cancer cells. Mol Med Rep. 13:4101–4107. 2016. View Article : Google Scholar : PubMed/NCBI
16	Hong H, Zheng JX, Liu L, Mai LX, Wei X and Wu LP: MicroRNA 21 and PLAP-1 regulate periodontal ligament remodeling during tooth movement of rats. Int J Clin Exp Pathol. 9:4943–4952. 2016.
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
18	Li Y, Jacox LA, Little SH and Ko CC: Orthodontic tooth movement: The biology and clinical implications. Kaohsiung J Med Sci. 34:207–214. 2018. View Article : Google Scholar : PubMed/NCBI
19	Khouw FE and Goldhaber P: Changes in vasculature of the periodontium associated with tooth movement in the rhesus monkey and dog. Arch Oral Biol. 15:1125–1132. 1970. View Article : Google Scholar : PubMed/NCBI
20	Franzen TJ, Brudvik P and Vandevska-Radunovic V: Periodontal tissue reaction during orthodontic relapse in rat molars. Eur J Orthod. 35:152–159. 2013. View Article : Google Scholar : PubMed/NCBI
21	Hou J, Chen Y, Meng X, Shi C, Li C, Chen Y and Sun H: Compressive force regulates ephrinB2 and EphB4 in osteoblasts and osteoclasts contributing to alveolar bone resorption during experimental tooth movement. Korean J Orthod. 44:320–329. 2014. View Article : Google Scholar : PubMed/NCBI
22	Wei F, Yang S, Xu H, Guo Q, Li Q, Hu L, Liu D and Wang C: Expression and function of hypoxia inducible factor-1α and vascular endothelial growth factor in pulp tissue of teeth under orthodontic movement. Mediators Inflamm. 2015:2157612015. View Article : Google Scholar : PubMed/NCBI
23	Jiang X, Zhang Y, Fan X, Deng X, Zhu Y and Li F: The effects of hypoxia-inducible factor (HIF)-1α protein on bone regeneration during distraction osteogenesis: An animal study. Int J Oral Maxillofac Surg. 45:267–272. 2016. View Article : Google Scholar : PubMed/NCBI
24	Wagegg M, Gaber T, Lohanatha FL, Hahne M, Strehl C, Fangradt M, Tran CL, Schönbeck K, Hoff P, Ode A, et al: Hypoxia promotes osteogenesis but suppresses adipogenesis of human mesenchymal stromal cells in a hypoxia-inducible factor-1 dependent manner. PLoS One. 7:e464832012. View Article : Google Scholar : PubMed/NCBI
25	Kulshreshtha R, Ferracin M, Wojcik SE, Garzon R, Alder H, Agosto-Perez FJ, Davuluri R, Liu CG, Croce CM, Negrini M, et al: A microRNA signature of hypoxia. Mol Cell Biol. 27:1859–1867. 2007. View Article : Google Scholar : PubMed/NCBI
26	Chen N, Sui BD, Hu CH, Cao J, Zheng CX, Hou R, Yang ZK, Zhao P, Chen Q, Yang QJ, et al: microRNA-21 contributes to orthodontic tooth movement. J Dent Res. 95:1425–1433. 2016. View Article : Google Scholar : PubMed/NCBI
27	Wei F, Liu D, Feng C, Zhang F, Yang S, Hu Y, Ding G and Wang S: microRNA-21 mediates stretch-induced osteogenic differentiation in human periodontal ligament stem cells. Stem Cells Dev. 24:312–319. 2015. View Article : Google Scholar : PubMed/NCBI
28	Chamila PPP, Samaranayake LP, Jin LJ and Zhang C: Periodontal ligament stem cells: An update and perspectives. J Investig Clin Dent. 5:81–90. 2014. View Article : Google Scholar : PubMed/NCBI
29	Meng YB, Li X, Li ZY, Zhao J, Yuan XB, Ren Y, Cui ZD, Liu YD and Yang XJ: microRNA-21 promotes osteogenic differentiation of mesenchymal stem cells by the PI3K/β-catenin pathway. J Orthop Res. 33:957–964. 2015. View Article : Google Scholar : PubMed/NCBI
30	Liu LL, Li D, He YL, Zhou YZ, Gong SH, Wu LY, Zhao YQ, Huang X, Zhao T, Xu L, et al: miR-210 protects renal cell against hypoxia-induced apoptosis by targeting HIF-1 alpha. Mol Med. 23:258–271. 2017. View Article : Google Scholar : PubMed/NCBI
31	Liu Y, Nie H, Zhang K, Ma D, Yang G, Zheng Z, Liu K, Yu B, Zhai C and Yang S: A feedback regulatory loop between HIF-1α and miR-21 in response to hypoxia in cardiomyocytes. FEBS Lett. 588:3137–3146. 2014. View Article : Google Scholar : PubMed/NCBI