•  
  •  
 

Abstract

Periodontitis is a disease marked by inflammation of the periodontium, caused by biofilms present in the oral cavity, and results in alveolar bone destruction. One of the main hallmarks of periodontitis is the presence of Aggregatibacter actinomycetecomitans, which is generally suppressed by antibiotic administration. The strategy to control A. actinomycetecomitans by small specific peptide inhibitors potentially halts the progression of alveolar bone damage while lowering the risk of antibiotic resistance. The detailed interaction mechanisms of A. actinomycetecomitans and bone cells are fundamental to discovering and constructing the specific inhibitor. Objective : To systematically review the mechanism of bone destruction by A. actinomycetecomitans based on its interaction with bone cells and its precursors. Methods: A comprehensive search was performed in two database (Scopus, PubMed) from September 2021 to June 2022, according to the Preferred Reporting Items for SystematicvReviews and Meta-Analyses (PRISMA) protocol. The terms used in the search were ”Aggregatibacter actinomycetemcomitans” OR “A. actinomycetemcomitans” AN” bone”OR “bone loss” OR “bone destruction” OR “bone resorption” OR “bone formation” OR “bone remodelling” OR “osteclast” OR “osteoblast” OR “osteocyte”. Only articles in English and research articles published within ten years were included. Results: In total, nine articles discussing alveolar bone destruction were included in the review. Most articles reported the virulence of A. actinomycetecomitans, lipopolysaccharide (LPS), and its target cells, osteoclast progenitors, osteoclasts, and osteoblasts. Conclusion: A. actinomycetecomitans induces alveolar bone destruction via various mechanisms, including osteoblast apoptosis, lowering osteoblast differentiation, increasing osteoclast activity and differentiation, and releasing inflammatory cytokines. The detailed interaction mechanisms between A. actinomycetecomitans and bone cells would provide valuable hints for further investigation toward constructing specific inhibitors to disrupt the interaction between A. actinomycetecomitans and bone cells that eventually protect the alveolar bone destruction.

References

1. Cardoso EM, Reis C, Manzanares-Céspedes MC. Chronic periodontitis, inflammatory cytokines, and interrelationship with other chronic diseases. Postgrad Med. 2018; 130(1):98-104.

2. How KY, Song KP, Chan KG. Porphyromonas gingivalis: An overview of periodontopathic pathogen below the gum line. Front Microbiol. 2016; 7(53):1-14.

3. Nygren P, Balashova N, Brown AC, Kieba I, Dhingra A, Boesze-Battaglia K, Lally ET. Agg regatibacter actinomycetemcomitans leukotoxin causes activation of lymphocyte function-associated antigen 1. Cell Microbiol. 2019; 21(3):e12967.

4. Herbert BA, Steinkamp HM, Gaestel M, Kirkwood KL. Mitogen-activated protein kinase 2 signaling shapes macrophage plasticity in Aggregatibacter actinomycetemcomitans-induced bone loss. Infect Immun. 2016; 85(1):e00552-16.

5. Dahlen G, Basic A, Bylund J. Importance of virulence factors for the persistence of oral bacteria in the inflamed gingival crevice and in the pathogenesis of periodontal disease. J Clin Med. 2019; 8(9):1339.

6. Silva N, Abusleme L, Bravo D, Dutzan N, Garcia- Sesnich J, Vernal R, Hernández M, Gamonal J. Host response mechanisms in periodontal diseases. J Appl Oral Sci. 2015; 23(3):329-55.

7. Hienz SA, Paliwal S, Ivanovski S. Mechanisms of bone resorption in periodontitis. J Immunol Res. 2015; 2015:1-10.

8. Benso B. Virulence factors associated with Aggregatibacter actinomycetemcomitans and their role in promoting periodontal diseases. Virulence. 2017; 8(2):111-4.

9. Belibasakis GN, Maula T, Bao K, Lindholm M, Bostanci N, Oscarsson J, et al. Virulence and pathogenicity properties of Aggregatibacter actinomycetemcomitans. Pathogens. 2019; 8(4):1- 23.

10. Gonçalves PF, Klepac-Ceraj V, Huang H, Paster BJ, Aukhil I, Wallet SM, Shaddox LM. Correlation of Aggregatibacter actinomycetemcomitans detection with clinical/immunoinflammatory profile of localized aggressive periodontitis using a 16S rRNA microarray method: A cross-sectional study. PLoS One. 2013; 8(12):e85066.

11. Lee HA, Park MH, Song Y, Na HS, Chung J. Role of Aggregatibacter actinomycetemcomitansinduced autophagy in inflammatory response. J Periodontol. 2020; 91(12):1682-93.

12. Settem RP, Honma K, Chinthamani S, Kawai T, Sharma A. B-cell RANKL contributes to pathogen-induced alveolar bone loss in an experimental periodontitis mouse model. Front Physiol. 2021; 12:722859.

13. Krauss JL, Roper PM, Ballard A, Shih C, Fitzpatrick JAJ, Ng PY, et al. Staphylococcus aureus infects Osteoclast and Replicates Intracellularly. 2019; 10(5):1-15.

14. Josse J, Velard F, Gangloff SC. Staphylococcus au reus vs. Osteoblast: Relat ionsh ip and consequences in Osteomyelitis. Front Cell Infect Microbiol. 2015; 5:85.

15. Yang D, Wijenayaka AR, Solomon LB, Pederson SM, Findlay DM, Kidd SP, Atkins GJ. Novel insights into Staphylococcus aureus Deep Bone Infections: the Involvement of Osteocytes. mBio. 2018; 9(2):e00415-18.

16. Trouillet-Assant S, Gallet M, Nauroy P, Rasigade JP, Flammier S, Parroche P, Marvel J, Ferry T, Vandenesch F, Jurdic P, Laurent F. Dual impact of live Staphylococcus aureus on the osteoclast lineage, leading to increased bone resorption. J Infect Dis. 2015; 211(4):571-81.

17. Flannagan RS, Heit B, Heinrichs DE. Intracellular replication of Staphylococcus aureus in mature phagolysosomes in macrophages precedes host cell death, and bacterial escape and dissemination. Cell Microbiol. 2016; 18(4):514-35.

18. Flannagan RS, Watson DW, Surewaard BGJ, Kubes P, Heinrichs DE. The surreptitious survival of the emerging pathogen Staphylococcus lugdunensis within macrophages as an immune evasion strategy. Cell Microbiol. 2018; 20(11):e12869.

19. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009; 6(7):1-6.

20. Xu J, Gong T, Heng BC, Zhang CF. A systematic review: Differentiation of stem cells into functional pericytes. FASEB J. 2017; 31(5):1775-86.

21. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research. PLoS Biol. 2010; 8(6):8-9.

22. Madeira MFM, Queiroz-Junior CM, Cisalpino D, Werneck SMC, Kikuchi H, Fujise O, et al. MyD88 is essential for alveolar bone loss induced by Aggregatibacter actinomycetemcomitans lipopolysaccharide in mice. Mol Oral Microbiol. 2013; 28(6):415-24.

23. Li X, Zhou L, Takai H, Sasaki Y, Mezawa M, Li Z, et al. Aggregatibacter actinomycetemcomitans Lipopolysaccharide Regulates Bone Sialoprotein Gene Transcription. J Cell Biochem. 2012; 113(9):2822-34.

24. Zhao P, Liu J, Pan C, Pan Y. NLRP3 inflammasome is required for apoptosis of Aggregatibacter act i nomycetemcom it ans-i nfected hu man osteoblastic MG63 cells. Acta Histochem. 2014; 116:1119-24.

25. Madeira MFM, Queiroz-Junior CM, Costa GM, Santos PC, Silveira EM, Garlet GP, et al. MIF induces osteoclast differentiation and contributes to progression of periodontal disease in mice. Microbes Infect. 2012; 14(2):198-206.

26. Madeira MFM, Queiroz-Junior CM, Costa GM, Werneck SMC, Cisalpino D, Garlet GP, et al. Plateletactivating factor receptor blockade ameliorates Aggregatibacter actinomycetemcomitans-Induced periodontal disease in mice. Infect Immun. 2013; 81(11):4244-51.

27. Yu H. Sphingosine-1-Phosphate Receptor 2 Regulates Proinflammatory Cytokine Production and Osteoclastogenesis. PLoS One. 2016; 11(5):1- 16.

28. Yu H, Sun C, Argraves KM. Periodontal inflammation and alveolar bone loss induced by Aggregatibacter actinomycetemcomitans is attenuated in sphingosine kinase 1-deficient mice. J Periodontal Res. 2016; 51(1):38-49.

29. Madeira MFM, Queiroz-Junior CM, Corrêa JD, Werneck SMC, Machado FS, Cunha TM, et al. The role of 5-lipoxygenase in Aggregatibacter actinomycetemcomitans-induced alveolar bone loss. J Clin Periodontol. 2017; 44(8):793-802.

30. Valerio MS, Herbert BA, Basilakos DS, Browne C, Yu H, Kirkwood KL. Critical role of MKP-1 in lipopolysaccharide-induced osteoclast formation through CXCL1 and CXCL2. Cytokine. 2015; 71(1):71-80.

31. Hbibi A, Bouziane A, Lyoussi B, Zouhdi M, Benazza D. Aggregatibacter actinomycetemcomitans: From basic to advanced research. Adv Exp Med Biol. 2022; 1373:45-67.

32. Könönen E, Müller HP. Microbiology of aggressive periodontitis. Periodontol 2000. 2014; 65(1):46-78.

33. Clark D, Febbraio M, Levin L. Aggressive periodontitis: The unsolved mystery. Quintessence Int. 2017; 48(2):103-11.

34. Kulkarni C, Kinane DF. Host response in aggressive periodontitis. Periodontol 2000. 2014; 65(1):79-91.

35. Nibali L. Aggressive periodontitis: Microbes and host response, who to blame? Virulence. 2015; 6(3):223-8.

36. Danforth DR, Melloni M, Tristano J, Mintz K P. Contribution of adhesion proteins to Aggregatibacter actinomycetemcomitans biofilm formation. Mol Oral Microbiol. 2021; 36(4):243-53.

37. Danforth DR, Tang-Siegel G, Ruiz T, Mintz KP. A Nonfimbrial adhesin of Aggregatibacter actinomycetemcomitans mediates biof ilm biogenesis. Infect Immun. 2018; 87(1):e00704-18.

38. Dentino A, Lee S, Mailhot J, Hefti AF. Principles of periodontology. Periodontology 2000. 2013; 61(1):16-53.

39. Kinane DF, Stathopoulou PG, Papapanou PN. Periodontal diseases. Nat Rev Dis Prim. 2017; 3:1-14.

40. Herbert BA, Steinkamp HM, Gaestel M, Kirkwood KL. Mitogen-activated protein kinase 2 signaling shapes macrophage plasticity in Aggregatibacter actinomycetemcomitans-induced bone loss. Infect Immun. 2016; 85(1):e00552-16.

41. Okinaga T, Ariyoshi W, Nishihara T. Aggregatibacter actinomycetemcomitans invasion induces Interleukin-1β production through reactive oxygen species and Cathepsin B. J Interferon Cytokine Res. 2015; 35(6):431-40.

42. Díaz-Zúñiga J, Melgar-Rodríguez S, Monasterio G, Pujol M, Rojas L, Alvarez C, Carvajal P, Vernal R. Differential human Th22-lymphocyte response triggered by Aggregatibacter actinomycetemcomitans serotypes. Arch Oral Biol. 2017; 78:26-33.

43. Vicencio E, Cordero EM, Cortés BI, Palominos S, Parra P, Mella T, Henrríquez C, Salazar N, Monasterio G, Cafferata EA, Murgas P, Vernal R, Cortez C. Aggregatibacter actinomycetemcomitans induces autophagy in human junctional epithelium keratinocytes. Cells. 2020; 9(5):1221.

44. Lee HA, Park MH, Song Y, Na HS, Chung J. Role of Aggregatibacter actinomycetemcomitansinduced autophagy in inflammatory response. J Periodontol. 2020; 91(12):1682-93.

45. Hiyoshi T, Domon H, Maekawa T, Nagai K, Tamura H, Takahashi N, Yonezawa D, Miyoshi T, Yoshida A, Tabeta K, Terao Y. Aggregatibacter actinomycetemcomitans induces detachment and death of human gingival epithelial cells and fibroblasts via elastase release following leukotoxin-dependent neutrophil lysis. Microbiol Immunol. 2019; 63(3-4):100-10.

46. Teshima R, Hanada K, Akada J, Kawano K, Yamaoka Y. Aggregatibacter actinomycetemcomitans infection causes DNA double-strand breaks in host cells. Genes Cells. 2018; 23(4):264-73.

47. Schröder A, Stumpf J, Paddenberg E, Neubert P, Schatz V, Köstler J, Jantsch J, Deschner J, Proff P, Kirschneck C. Effects of mechanical strain on periodontal ligament fibroblasts in presence of Aggregatibacter actinomycetemcomitans lysate. BMC Oral Health. 2021; 21(1):405.

48. Ozuna H, Uriarte SM, Demuth DR. The Hunger Games: Aggregatibacter actinomycetemcomitans exploits human neutrophils as an epinephrine source for survival. Front Immunol. 2021; 12:707096.

49. Gholizadeh P, Pormohammad A, Eslami H, Shokouhi B, Fakhrzadeh V, Kafil HS. Oral pathogenesis of Aggregatibacter actinomycetemcomitans. Microb Pathog. 2017; 113(2017):303-11.

50. Fine DH, Patil AG, Velusamy SK. Aggregatibacter actinomycetemcomitans (Aa) under the radar: Myths and misunderstandings of Aa and its role in aggressive periodontitis. Front Immunol. 2019; 10:728.

51. Oscarsson J, Claesson R, Lindholm M, Aberg CHÅ, Johanson A. Tools of Aggregatibacter actinomycetemcomitans to evade the host response. J Clin Med. 2019; 8:1079.

52. Monasterio G, Castillo F, Astorga J, Hoare A, Terraza-Aguirre C, Cafferata EA, Villablanca EJ, Vernal R. O-polysaccharide plays a major role on the virulence and immunostimulatory potential of Aggregatibacter actinomycetemcomitans during periodontal infection. Front Immunol. 2020 11:591240.

53. Johansson A, Buhlin K, Sorsa T, Pussinen PJ. Systemic Aggregatibacter actinomycetemcomitans Leukotoxin-neutralizing antibodies in periodontitis. J Periodontol. 2017; 88(1):122-9.

54. Damgaard C, Danielsen AK, Enevold C, Reinholdt J, Holmstrup P, Nielsen CH, Massarenti L. Circulating antibodies against leukotoxin A as marker of periodontitis Grades B and C and oral infection with Aggregatibacter actinomycetemcomitans. J Periodontol. 2021; 92(12):1795-804.

55. Vega BA, Schober LT, Kim T, Belinka BA Jr, Kachlany SC. Aggregatibacter actinomycetemcomitans Leukotoxin (LtxA) Requires Death Receptor Fas, in Addition to LFA-1, To Trigger Cell Death in T Lymphocytes. Infect Immun. 2019; 87(8):e00309-19.

56. Cappariello A, Maurizi A, Veeriah V, Teti A. The great beauty of the osteoclast. Arch Biochem Biophys. 2014; 558:70-8.

57. Cortelli JR, Cortelli SC, Aquino DR, Miranda TB, Jardim JCM, Costa FO. Aggregatibacter actinomycetemcomitans serotypes and JP2 outcomes related to clinical status over 6 years under periodontal maintenance therapy. Arch Oral Biol. 2020; 116:104747.

58. Rojas L, Melgar-Rodríguez S, Díaz-Zúñiga J, Alvarez C, Monasterio G, Rojas C, Cafferata EA, Hernández M, Cortéz C, Carvajal P, Vernal R.Inhibitory effect of serotype a of Aggregatibacter actinomycetemcomitans on the increased destructive potential of serotype b. Oral Dis. 2020; 26(2):409-18.

59. Rebeis ES, Albuquerque-Souza E, Paulino da Silva M, Giudicissi M, Mayer MPA, Saraiva L. Effect of periodontal treatment on Aggregatibacter actinomycetemcomitans colonization and serum IgG levels against A. actinomycetemcomitans serotypes and Omp29 of aggressive periodontitis patients. Oral Dis. 2019; 25(2):569-79.

60. Rojas L, Melgar-Rodríguez S, Díaz-Zúñiga J, Alvarez C, Monasterio G, Rojas C, Carvajal P, Vernal R. Serotype a of Aggregatibacter actinomycetemcomitans down-regulates the increased serotype b-induced cytokine and chemokine production in dendritic cells. Arch Oral Biol. 2018; 93:155-62.

61. Brígido JA, da Silveira VR, Rego RO, Nogueira NA. Serotypes of Aggregatibacter actinomycetemcomitans in relation to periodontal status and geographic origin of individuals-a review of the literature. Med Oral Patol Oral Cir Bucal. 2014; 19(2):e184-91.

62. Ennibi OK, Claesson R, Akkaoui S, Reddahi S, Kwamin F, Haubek D, Johansson A. High salivary levels of JP2 genotype of Aggregatibacter actinomycetemcomitans is associated with clinical attachment loss in Moroccan adolescents. Clin Exp Dent Res. 2019; 5(1):44-51.



Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.