Orthodontic treatment induces Th17/Treg cells to regulate tooth movement in rats with periodontitis

Document Type : Original Article


1 Department of Orthodontics, Beijing Stomatological Hospital & School of Stomatology, Capital Medical University, Beijing 100050, China

2 Department of Stomatology, Beijing Pinggu Hospital, Beijing 101200, China

3 Department of Orthodontics, Stomatological Hospital of Guangzhou Medical University, Guangzhou 100079, China

4 Department of Stomatology, Tie Ying Hospital of Fengtai District Beijing, Beijing 100079, China

5 Institute of dental Research, Beijing Stomatological Hospital & School of Stomatology, Capital Medical University, Beijing 100050, China


Objective(s): Here we investigated the regulation of Th17 and Treg cells in orthodontic tooth movement during periodontal inflammation.
Materials and Methods: Fifty-six SD rats were divided into a control (24 rats) and a tooth movement group during the recovery stage of periodontitis (RM group, 32 rats). Periodontitis was established by silk ligation and local injection of LPS. Orthodontic tooth movement was achieved by nickel-titanium springs on the maxillary first molars. The proportions of Th17 cells and Treg cells were evaluated by flow cytometry. Gene expression of ROR-γt and Foxp3 was determined by real-time PCR. Expression of ROR-γt, Foxp3, RANK, RANKL, and OPG was detected by immunohistochemical staining. Osteoclasts were detected by TRAP staining. Relationships between Th17/Treg cells, osteoclasts, and related factors were estimated by correlation and regression analysis.
Results: During orthodontic tooth movement in the recovery stage of periodontitis, the proportion of Th17 cells, ROR-γt, RANK, osteoclasts, and the RANKL/OPG ratio increased and then decreased. The proportion of Treg cells and Foxp3 increased, then decreased, and increased again. Levels of RANKL and OPG increased, then decreased, then increased, and finally decreased. The Th17/Treg ratio initially decreased, then increased, and decreased again. Th17 cells were positively correlated with RANK and RANKL, the RANKL/OPG ratio, and counts of osteoclasts. Treg cells were negatively correlated with RANK expression and numbers of osteoclasts. The Th17/Treg ratio was positively correlated with RANK expression and numbers of osteoclasts.
Conclusion: Under periodontal inflammation conditions, the Th17/Treg ratio might regulate orthodontic tooth movement through changing osteoclasts metabolism.


1. Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol 2015; 15:30-44.
2. Lavu V, Venkatesan V, Rao SR. The epigenetic paradigm in periodontitis pathogenesis. J Indian Soc Periodontol 2015; 19:142-149.
3. Maeda S, Maeda Y, Ono Y, Nakamura K, Sasaki T. Interdisciplinary treatment of a patient with severe pathologic tooth migration caused by Localized aggressive periodontitis. Am J Orthod Dentofacial Orthop 2005; 127:374-384.
4. Gkantidis N, Christou P, Topouzelis N. The orthodontic—periodontic interrelationship in integrated treatment challenges: a systematic review. J Oral Rehabil 2010; 37:377-390.
5. Hernandez M, Dutzan N, Garcia-Sesnich J, Abusleme L, Dezerega A, Silva N, et al. Host-pathogen interactions in progressive chronic periodontitis. J Dent Res 2011; 90:1164-1170.
6. Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol 2010; 40:1830-1835.
7. Hienz SA, Paliwal S, Ivanovski S. Mechanisms of bone resorption in periodontitis. J Immunol Res 2015; 2015:615486.
8. Cardoso CR, Garlet GP, Moreira AP, Júnior WM, Rossi MA, Silva JS. Characterization of CD4+CD25+ natural regulatory T cells in the inflammatory infiltrate of human chronic periodontitis. J Leukoc Biol 2008; 84:311-318.
9. Karthikeyan B, Talwar, Arun KV, Kalaivani S. Evaluation of transcription factor that regulates T helper 17 and regulatory T cells function in periodontal health and disease. J Pharm Bioallied Sci 2015; 7: S672–S676.
10. Ge N, Yu N, Chen L. The preliminary study on the changes of Thl7/Treg cell balance in different stages of periodontitis. Beijing Journal of Stomatology 2019; 27:132-136.
11. de Aquino SG, Guimaraes MR, Stach-Machado DR, da Silva JA, Spolidorio LC, Rossa C Jr. Differential regulation of mmp-13 expression in two models of experimentally induced periodontal disease in rats. Arch Oral Biol 2009; 54:609-617.
12. Arun T, Sayinsu K, Nalbantgil D. Orthodontic approach for patients with severe periodontal disease. World J orthod 2005; 6:275-280.
13. Llavaneras A, Ramamurthy NS, Heikkilä P, Teronen O, Salo T, Rifkin BR, et al. A combination of a chemically modified doxycycline and a bisphosphonate synergistically inhibits endotoxin-induced periodontal breakdown in rats. J Periodontol 2001; 72:1069-1077.
14. Cardoso CR, Garlet GP, Crippa GE, Rosa AL, Junior WM, Rossi MA, et al. Evidence of thepresence of T helper type 17 cells in chronic lesions of human periodontal disease. Oral Microbiol Immunol 2009; 24:1-6.
15. Zhao L, Zhou Y, Xu Y, Sun Y, Li L, Chen W. Effect of non-surgical periodontal therapy on the levels of Th17/Th1/Th2 cytokines and their transcription factors in Chinese chronic periodontitis patients. J Clin Periodontol 2011; 38:509-516.
16. Gao L, Zhao Y, Wang P, Zhang L, Zhang C, Chen Q, et al. Detection of Th17/Treg cells and related factors in gingival tissues and peripheral blood of rats with experimental periodontitis. Iran J Basic Med Sci 2017; 20:294-300.
17. Ohlrich EJ, Cullinan MP, Seymour GJ. The immunopathogenesis of periodontal disease. Aust Dent J 2009; 54:S2-S10.
18. Wang L, Wang J, Jin Y, Gao H, Lin X. Oral administration of all-trans retinoic acid suppresses experimental periodontitis by Modulating the Th17/Treg Imbalance. J Periodontol 2014; 85:740-750.
19. Yamaguchi M, Garlet GP. The role of inflammation in defining the type and pattern of tissue response in orthodontic tooth movement. Biological Mechanisms of Tooth Movement. 2nd ed. Wiley; 2015.
20. Okamoto A, Ohnishi T, Bandow K, Kakimoto K, Chiba N, Maeda A, et al. Reduction of orthodontic tooth movement by experimentally induced periodontal inflammation in mice. Eur J Oral Sci 2009; 117:238-247.
21. Lubberts E, van den Bersselaar L, Oppers-Walgreen B, Schwarzenberger P, Coenen-de Roo CJ, Kolls JK, et al. IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-kappa B ligand/ osteoprotegerin balance.J Immunol 2003; 170:2655-2662.
22. Zhang F, Tanaka H, Kawato T, Kitami S, Nakai K, Motohashi M, et al. Interleukin-17A induces cathepsin K and MMP-9 expression in osteoclasts via celecoxib-blocked prostaglandin E2 in osteoblasts. Biochimie 2011; 93:296-305.
23. Kim KW, Kim HR, Kim BM, Cho ML, Lee SH. Th17 cytokines regulate osteoclastogenesis in rheumatoid arthritis. Am J Pathol 2015; 185:3011-3024.
24. Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc NatI Acad Sci U S A 1999; 96:3540-3545.
25. Mohamed SG, Sugiyama E, Shinoda K, Taki H, Hounoki H, Abdel-Aziz HO, et al. Interleukin-10 inhibits RANKL-mediated expression of NFATc1 in part via suppression of c-Fos and c-Jun in RAW264.7 cells and mouse bone marrow cells. Bone 2007; 41:592-602.
26. Axmann R, Herman S, Zaiss M, Franz S, Polzer K, Zwerina J, et al. CTLA-4 directly inhibits osteoclast formation. Ann Rheum Dis 2008; 67:1603-1609.
27. Zaiss MM, Axmann R, Zwerina J, Polzer K, Gückel E, Skapenko A, et al. Treg cells suppress osteoclast formation: A new link between the immune system and bone. Arthritis Rheum 2007; 56:4104-4112.