Skip to main content

Advertisement

SpringerLink
Log in

Glipizide Alleviates Periodontitis Pathogenicity via Inhibition of Angiogenesis, Osteoclastogenesis and M1/M2 Macrophage Ratio in Periodontal Tissue

  • RESEARCH
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

New consensus indicates type 2 diabetes mellitus (T2DM) and periodontitis as comorbidity and may share common pathways of disease progression. Sulfonylureas have been reported to improve the periodontal status in periodontitis patients. Glipizide, a sulfonylurea widely used in the treatment of T2DM, has also been reported to inhibit inflammation and angiogenesis. The effect of glipizide on the pathogenicity of periodontitis, however, has not been studied. We developed ligature-induced periodontitis in mice and treated them with different concentrations of glipizide and then analyzed the level of periodontal tissue inflammation, alveolar bone resorption, and osteoclast differentiation. Inflammatory cell infiltration and angiogenesis were analyzed using immunohistochemistry, RT-qPCR, and ELISA. Transwell assay and Western bolt analyzed macrophage migration and polarization. 16S rRNA sequencing analyzed the effect of glipizide on the oral microbial flora. mRNA sequencing of bone marrow-derived macrophages (BMMs) stimulated by P. gingivalis lipopolysaccharide (Pg-LPS) after treatment with glipizide was analyzed. Glipizide decreases alveolar bone resorption, periodontal tissue degradation, and the number of osteoclasts in periodontal tissue affected by periodontitis (PAPT). Glipizide-treated periodontitis mice showed reduced micro-vessel density and leukocyte/macrophage infiltration in PAPT. Glipizide significantly inhibited osteoclast differentiation in vitro experiments. Glipizide treatment did not affect the oral microbiome of periodontitis mice. mRNA sequencing and KEGG analysis showed that glipizide activated PI3K/AKT signaling in LPS-stimulated BMMs. Glipizide inhibited the LPS-induced migration of BMMs but promoted M2/M1 macrophage ratio in LPS-induced BMMs via activation of PI3K/AKT signaling. In conclusion, glipizide inhibits angiogenesis, macrophage inflammatory phenotype, and osteoclastogenesis to alleviate periodontitis pathogenicity suggesting its’ possible application in the treatment of periodontitis and diabetes comorbidity.

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

Data Availability

The datasets generated and/or analyzed during the current study are available from the corresponding authors on reasonable request.

References

  1. Yang, L., et al. 2021. Sulfonylureas for treatment of periodontitis-diabetes comorbidity-related complications: Killing two birds with one stone. Frontiers in Pharmacology 12: 728458.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Gasner, N.S. and R.S. Schure. 2022. Periodontal disease, in StatPearls. 2022, StatPearls Publishing Copyright ©, StatPearls Publishing LLC.: Treasure Island (FL).

  3. Wang, L., et al. 2020. SLIT2 overexpression in periodontitis intensifies inflammation and alveolar bone loss, possibly via the activation of MAPK pathway. Frontiers in Cell and Development Biology 8: 593.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Bui, F.Q., et al. 2019. Association between periodontal pathogens and systemic disease. Biomedical Journal 42 (1): 27–35.

    PubMed  PubMed Central  Google Scholar 

  5. Hajishengallis, G. 2020.  New developments in neutrophil biology and periodontitis. Periodontology 2000 82 (1): 78–92.

    PubMed  Google Scholar 

  6. Löe, H. 1993. Periodontal disease. The sixth complication of diabetes mellitus. Diabetes Care 16 (1): 329–34.

    PubMed  Google Scholar 

  7. Graves, D.T., Z. Ding, and Y. Yang. 2000. The impact of diabetes on periodontal diseases. Periodontology 2000 82 (1): 214–224.

    Google Scholar 

  8. Shi, B., et al. 2020. The subgingival microbiome associated with periodontitis in type 2 diabetes mellitus. ISME Journal 14 (2): 519–530.

    CAS  PubMed  Google Scholar 

  9. Teles, R., and C.Y. Wang. 2011. Mechanisms involved in the association between periodontal diseases and cardiovascular disease. Oral Diseases 17 (5): 450–461.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Mammen, M.J., F.A. Scannapieco, and S. Sethi. 2020. Oral-lung microbiome interactions in lung diseases. Periodontology 2000 83 (1): 234–241.

    PubMed  Google Scholar 

  11. Lalla, E., and P.N. Papapanou. 2011. Diabetes mellitus and periodontitis: A tale of two common interrelated diseases. Nature Reviews. Endocrinology. 7 (12): 738–748.

    CAS  PubMed  Google Scholar 

  12. Lv, W., et al. 2020. Mechanisms and characteristics of sulfonylureas and glinides. Current Topics in Medicinal Chemistry 20 (1): 37–56.

    CAS  PubMed  Google Scholar 

  13. Fernandez, C.J., A.V. Raveendran, and N. Htwe. 2021. Efficacy and cardiovascular safety of sulfonylureas. Current Drug Safety 16 (2): 142–153.

    CAS  PubMed  Google Scholar 

  14. Araújo, A.A., et al. 2019. Gliclazide reduced oxidative stress, inflammation, and bone loss in an experimental periodontal disease model. Journal of Applied Oral Science 27: e20180211.

    PubMed  PubMed Central  Google Scholar 

  15. Kawahara, Y., et al. 2020. Effects of sulfonylureas on periodontopathic bacteria-induced inflammation. Journal of Dental Research 99 (7): 830–838.

    CAS  PubMed  Google Scholar 

  16. Correa, R., B.S. Quintanilla Rodriguez, and T.M. Nappe. 2022. Glipizide in StatPearls. StatPearls Publishing. Copyright © 2022, StatPearls Publishing LLC.: Treasure Island (FL). Copyright © 2022, StatPearls Publishing LLC.: Treasure Island (FL).

  17. Qi, C., et al. 2014. Glipizide, an antidiabetic drug, suppresses tumor growth and metastasis by inhibiting angiogenesis. Oncotarget 5 (20): 9966–9979.

    PubMed  PubMed Central  Google Scholar 

  18. Moreau, R., et al. 1997. Pharmacological and biochemical evidence for the regulation of osteocalcin secretion by potassium channels in human osteoblast-like MG-63 cells. Journal of Bone and Mineral Research 12 (12): 1984–1992.

    CAS  PubMed  Google Scholar 

  19. Joya-Galeana, J., et al. 2011. Effects of insulin and oral anti-diabetic agents on glucose metabolism, vascular dysfunction and skeletal muscle inflammation in type 2 diabetic subjects. Diabetes/Metabolism Research and Reviews 27 (4): 373–382.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Sima, C., A. Viniegra, and M. Glogauer. 2019. Macrophage immunomodulation in chronic osteolytic diseases-the case of periodontitis. Journal of Leukocyte Biology 105 (3): 473–487.

    CAS  PubMed  Google Scholar 

  21. Kubatzky, K.F., F. Uhle, and T. Eigenbrod. 2018. From macrophage to osteoclast - how metabolism determines function and activity. Cytokine 112: 102–115.

    CAS  PubMed  Google Scholar 

  22. Pereira, M., et al.2018. Common signalling pathways in macrophage and osteoclast multinucleation. Journal of Cell Science 131 (11).

  23. Yunna, C., et al. 2020. Macrophage M1/M2 polarization. European Journal of Pharmacology 877: 173090.

    PubMed  Google Scholar 

  24. Pathak, J.L., et al. 2021. Downregulation of macrophage-specific Act-1 intensifies periodontitis and alveolar bone loss possibly via TNF/NF-κB signaling. Frontiers in Cell Development Biology 9:628139.

    PubMed  PubMed Central  Google Scholar 

  25. Zhuang, Z., et al. 2019. Induction of M2 macrophages prevents bone loss in murine periodontitis models. Journal of Dental Research 98 (2): 200–208.

    CAS  PubMed  Google Scholar 

  26. Li, C., M. Levin, and D.L. Kaplan. 2016. Bioelectric modulation of macrophage polarization. Science and Reports 6: 21044.

    CAS  Google Scholar 

  27. Lin, Y.W., et al. 2018. Glyburide and retinoic acid synergize to promote wound healing by anti-inflammation and RIP140 degradation. Science and Reports 8 (1): 834.

    Google Scholar 

  28. Kewcharoenwong, C., et al. 2018. Glibenclamide reduces primary human monocyte functions against tuberculosis infection by enhancing M2 polarization. Frontiers in Immunology 9: 2109.

    PubMed  PubMed Central  Google Scholar 

  29. Abe, T., and G. Hajishengallis. 2013. Optimization of the ligature-induced periodontitis model in mice. Journal of Immunological Methods 394 (1–2): 49–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang, L., et al. 2022. SAP deficiency aggravates periodontitis possibly via C5a-C5aR signaling-mediated defective macrophage phagocytosis of Porphyromonas gingivalis. Journal of Advanced Research.

  31. Hu, L., et al. 2022. MiR-1224-5p modulates osteogenesis by coordinating osteoblast/osteoclast differentiation via the Rap1 signaling target ADCY2. Experimental & Molecular Medicine 54 (7): 961–972.

    CAS  Google Scholar 

  32. Xiao, E., et al. 2017. Diabetes enhances IL-17 expression and alters the oral microbiome to increase its pathogenicity. Cell Host & Microbe 22 (1): 120-128.e4.

    CAS  Google Scholar 

  33. Spiller, K.L., et al. 2016. Differential gene expression in human, murine, and cell line-derived macrophages upon polarization. Experimental Cell Research 347 (1): 1–13.

    CAS  PubMed  Google Scholar 

  34. Zhao, B. 2020. Intrinsic restriction of TNF-mediated inflammatory osteoclastogenesis and bone resorption. Front Endocrinol (Lausanne) 11: 583561.

    PubMed  Google Scholar 

  35. Sheethal, H.S., et al. 2018. Role of mast cells in inflammatory and reactive pathologies of pulp, periapical area and periodontium. J Oral Maxillofac Pathol 22 (1): 92–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Yan, X., et al. 2020. Uncoupling protein-2 regulates M1 macrophage infiltration of gingiva with periodontitis. Cent Eur J Immunol 45 (1): 9–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Li, J., et al. 2021. 2D MOF periodontitis photodynamic ion therapy. Journal of the American Chemical Society 143 (37): 15427–15439.

    CAS  PubMed  Google Scholar 

  38. Curtis, M.A., P.I. Diaz, and T.E. Van Dyke. 2020. The role of the microbiota in periodontal disease. Periodontology 2000 83 (1): 14–25.

    PubMed  Google Scholar 

  39. Gu, Y., et al. 2017. Analyses of gut microbiota and plasma bile acids enable stratification of patients for antidiabetic treatment. Nature Communications 8 (1): 1785.

    PubMed  PubMed Central  Google Scholar 

  40. Ma, P., et al. 2010. Glimepiride induces proliferation and differentiation of rat osteoblasts via the PI3-kinase/Akt pathway. Metabolism 59 (3): 359–366.

    CAS  PubMed  Google Scholar 

  41. Ma, P., et al. 2014. Glimepiride promotes osteogenic differentiation in rat osteoblasts via the PI3K/Akt/eNOS pathway in a high glucose microenvironment. PLoS ONE 9 (11): e112243.

    PubMed  PubMed Central  Google Scholar 

  42. Park, S.Y., et al. 2011. Schisandra chinensis α-iso-cubebenol induces heme oxygenase-1 expression through PI3K/Akt and Nrf2 signaling and has anti-inflammatory activity in Porphyromonas gingivalis lipopolysaccharide-stimulated macrophages. International Immunopharmacology 11 (11): 1907–1915.

    CAS  PubMed  Google Scholar 

  43. Ying, Y., and J. Luo. 2018. Salidroside promotes human periodontal ligament cell proliferation and osteocalcin secretion via ERK1/2 and PI3K/Akt signaling pathways. Experimental and Therapeutic Medicine 15 (6): 5041–5045.

    PubMed  PubMed Central  Google Scholar 

  44. Almubarak, A., et al. 2020. Disruption of monocyte and macrophage homeostasis in periodontitis. Frontiers in Immunology 11: 330.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Sun, X., et al. 2021. Polarized macrophages in periodontitis: Characteristics, function, and molecular signaling. Frontiers in Immunology 12: 763334.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Yuan, H., et al. 2017. Osteoclast stimulatory transmembrane protein induces a phenotypic switch in macrophage polarization suppressing an M1 pro-inflammatory state. Acta Biochimica et Biophysica Sinica (Shanghai) 49 (10): 935–944.

    CAS  Google Scholar 

  47. Hasegawa, T., et al. 2019. Identification of a novel arthritis-associated osteoclast precursor macrophage regulated by FoxM1. Nature Immunology 20 (12): 1631–1643.

    CAS  PubMed  Google Scholar 

  48. Lebovitz, H.E. 1985. Glipizide: a second-generation sulfonylurea hypoglycemic agent. Pharmacology, pharmacokinetics and clinical use. Pharmacotherapy 5 (2): 63–77.

    CAS  PubMed  Google Scholar 

  49. Qi, C., et al. 2016. Glipizide suppresses prostate cancer progression in the TRAMP model by inhibiting angiogenesis. Science and Reports 6: 27819.

    CAS  Google Scholar 

  50. Lange, M., et al. 2007. Continuously infused glipizide reverses the hyperdynamic circulation in ovine endotoxemia. Shock 27 (6): 701–706.

    CAS  PubMed  Google Scholar 

  51. Sakalauskiene, J., et al. 2016. Peripheral blood leukocytes interleukin-1 beta (IL-1β) cytokine hyper-reactivity in chronic periodontitis. Medical Science Monitor 22: 4323–4329.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Shi, D., et al. 2008. Systemic inflammation markers in patients with aggressive periodontitis: A pilot study. Journal of Periodontology 79 (12): 2340–2346.

    PubMed  Google Scholar 

  53. Parisi, L., et al. 2018. Macrophage polarization in chronic inflammatory diseases: Killers or builders? Journal of Immunology Research 2018: 8917804.

    PubMed  PubMed Central  Google Scholar 

  54. Vergadi, E., et al. 2017. Akt signaling pathway in macrophage activation and M1/M2 polarization. The Journal of Immunology 198 (3): 1006–1014.

    CAS  PubMed  Google Scholar 

  55. Wang, Y., et al. 2021. Quercetin-loaded ceria nanocomposite potentiate dual-directional immunoregulation via macrophage polarization against periodontal inflammation. Small (Weinheim an der Bergstrasse, Germany) 17 (41): e2101505.

    PubMed  Google Scholar 

  56. Liu, L., et al. 2019. Sirt1 ameliorates monosodium urate crystal-induced inflammation by altering macrophage polarization via the PI3K/Akt/STAT6 pathway. Rheumatology (Oxford) 58 (9): 1674–1683.

    CAS  PubMed  Google Scholar 

  57. Hajishengallis, G. 2015. Periodontitis: From microbial immune subversion to systemic inflammation. Nature Reviews Immunology 15 (1): 30–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Garrido-Mesa, N., A. Zarzuelo, and J. Gálvez. 2013. Minocycline: Far beyond an antibiotic. British Journal of Pharmacology 169 (2): 337–352.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by the National Natural Science Foundation of China (82150410451), the Basic and Applied Basic Research Foundation of Guangdong Province (2021A1515110988), the Project of Guangzhou Science and Technology Bureau (202002030301), Guangzhou City Clinical Key Specialty Cultivation Project (2021115257), and High-Level University Construction Funding of Guangzhou Medical University (02–410-B205001293, B195002003017, 02–412-B205002-1003017, and 06–410-2106035).

Author information

Author notes

  1. Xueqi Guo, Zhijun Huang, and Qing Ge contributed equally and share the first authorship.

Authors and Affiliations

  1. Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, 510182, Guangdong, China

    Xueqi Guo, Zhijun Huang, Qing Ge, Luxi Yang, Dongliang Liang, Yinyin Huang, Yiqin Jiang, Janak Lal. Pathak & Linhu Ge

  2. School of Life Sciences and Biopharmaceutics, Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China

    Lijing Wang

Authors
  1. Xueqi Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhijun Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qing Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luxi Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dongliang Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yinyin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yiqin Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Janak Lal. Pathak
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lijing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Linhu Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Xueqi Guo: conceptualization, data curation, and writing, original draft. Zhijun Huang: conceptualization, data curation, and writing, original draft. Qing Ge: conceptualization, data curation, and writing, original draft. Luxi Yang: investigation, methodology, formal analysis, and software interpreted data. Dongliang Liang: investigation, methodology, formal analysis, and software interpreted data. Yinyin Huang: investigation, methodology, formal analysis, and software interpreted data. Yiqin Jiang: investigation, methodology, formal analysis, and software interpreted data. Janak Lal Pathak: formal analysis, supervision, and writing, review and editing. Lijing Wang: formal analysis, supervision, and writing, review and editing. Linhu Ge: conceptualization, funding acquisition, supervision, validation, and writing, review and editing.

Corresponding author

Correspondence to Linhu Ge.

Ethics declarations

Competing Interests

The authors declare no competing interests.

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 (DOCX 584 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, X., Huang, Z., Ge, Q. et al. Glipizide Alleviates Periodontitis Pathogenicity via Inhibition of Angiogenesis, Osteoclastogenesis and M1/M2 Macrophage Ratio in Periodontal Tissue. Inflammation 46, 1917–1931 (2023). https://doi.org/10.1007/s10753-023-01850-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-023-01850-1

KEY WORDS

Search

Navigation