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Abstract

Periodontal diseases are a group of chronic, immune-mediated inflammatory conditions affecting the periodontium, the supportive structures of the teeth. With severe forms affecting nearly 20% of the worldwide adult population, these diseases represent a significant global health challenge. Their impact extends beyond the oral cavity, as periodontitis is a recognized risk factor for systemic conditions like cardiovascular disease and diabetes mellitus. Characterized by the progressive destruction of tooth-supporting tissues, early diagnosis is crucial to prevent tooth loss. However, conventional diagnostic methods primarily quantify historical tissue damage rather than indicating current disease activity or predicting future progression. To overcome these limitations, research has focused on biomarkers, objectively measured characteristics that can indicate normal biological processes or pathogenic states. Saliva has emerged as a promising diagnostic biofluid for such analysis, due to its non-invasive collection and rich composition of biomolecules. This review evaluates the potential of three functionally distinct salivary biomarkers. Evidence suggests that levels of matrix metalloproteinase-7, an epithelial-derived enzyme involved in tissue remodeling, are elevated in periodontitis, indicating active tissue degradation. Conversely, mucin-4, a transmembrane protein that forms a protective barrier, is consistently found at lower concentrations in saliva, suggesting a compromised or degraded mucosal shield. The role of human beta-defensin 1, a constitutively expressed antimicrobial peptide involved in innate immunity, remains ambiguous due to inconsistent findings across studies. While these salivary biomarkers show considerable promise, large-scale validation studies are essential to confirm their clinical utility for early diagnosis, risk assessment, and monitoring of periodontal diseases.

References

1] Loe € H, Anerud A, Boysen H, Morrison E. Natural history of periodontal disease in man. J Clin Periodontol 1986;13: 431—40. https://doi.org/10.1111/J.1600-051X.1986.TB01487.X.

[2] Page RC, Kornman KS. The pathogenesis of human periodontitis: an introduction. Periodontol 2000 1997;14:9—11. https://doi.org/10.1111/j.1600-0757.1997.tb00189.x.

[3] Chambrone L, Chambrone D, Lima LA, Chambrone LA. Predictors of tooth loss during long-term periodontal maintenance: a systematic review of observational studies. J Clin Periodontol 2010;37:675—84. https://doi.org/10.1111/J. 1600-051X.2010.01587.X.

[4] Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet 2005;366:1809—20. https://doi.org/10.1016/ S0140-6736(05)677

. [5] Dye BA. Global periodontal disease epidemiology. Periodontol 2000 2012;58:10—25. https://doi.org/10.1111/J.1600- 0757.2011.00413.X.

[6] Ma KS, Hasturk H, Carreras I, Dedeoglu A, Veeravalli JJ, Huang JY, et al. Dementia and the risk of periodontitis: a population-based cohort study. J Dent Res 2022;101:270—7. https://doi.org/10.1177/00220345211037220/SUPPL_FILE/SJPDF-1-JDR-10.1177_00220345211037220.PDF.

[7] Socransky SS, Haffajee AD. Periodontal microbial ecology. Periodontol 2000 2005;38:135—87. https://doi.org/10.1111/j. 1600-0757.2005.00107.x.

[8] Darveau RP. Periodontitis: a polymicrobial disruption of host homeostasis. Nat Rev Microbiol 2010;8(7):481—90. https://doi.org/10.1038/nrmicro2337.

[9] Loos BG, Van Dyke TE. The role of inflammation and genetics in periodontal disease. Periodontol 2000 2020;83: 26—39. https://doi.org/10.1111/PRD.12297.

[10] Cekici A, Kantarci A, Hasturk H, Van Dyke TE. Inflammatory and immune pathways in the pathogenesis of periodontal disease. Periodontol 2000 2014;64:57—80. https://doi. org/10.1111/PRD.12002.

[11] Lunar Silva I, Cascales E. Molecular strategies underlying porphyromonas gingivalis virulence. J Mol Biol 2021;433: 166836. https://doi.org/10.1016/j.jmb.2021.166836.

[12] Tonetti MS, Greenwell H, Kornman KS. Staging and grading of periodontitis: Framework and proposal of a new classification and case definition. J Periodontol 2018;89. https://doi.org/10.1002/JPER.18-0006.

[13] Ramenzoni LL, Lehner MP, Kaufmann ME, Wiedemeier D, Attin T, Schmidlin PR. Oral Diagnostic Methods for the Detection of Periodontal Disease. Diagnostics (Basel) 2021; 11. https://doi.org/10.3390/diagnostics11030571.

[14] Salvi GE, Roccuzzo A, Imber JC, Sta€hli A, Klinge B, Lang NP. Clinical periodontal diagnosis. Periodontol 2000 2023;00:1—19. https://doi.org/10.1111/PRD.12487. REQUESTEDJOURNAL:JOURNAL:16000757;PAGE: STRING:ARTICLE/CHAPTER.

[15] Goodson JM, Tanner ACR, Haffajee AD, Sornberger GC, Socransky SS. Patterns of progression and regression of advanced destructive periodontal disease. J Clin Periodontol 1982;9:472—81. https://doi.org/10.1111/J.1600- 051X.1982.TB02108.X.

[16] Kc S, Wang XZ, Gallagher JE. Diagnostic sensitivity and specificity of host-derived salivary biomarkers in periodontal disease amongst adults: systematic review. J Clin Periodontol 2020;47:289—308. https://doi.org/10.1111/jcpe. 13218.

[17] Ramachandra SS, Mehta DS, Sandesh N, Baliga V, Amarnath J. Periodontal probing systems: a review of available equipment. Compend Contin Educ Dent 2011;32: 71—7.

[18] Dobbs MB, Buckwalter J, Saltzman C. Osteoporosis: the increasing role of the orthopaedist. Iowa Orthop J 1999;19: 43—52.

[19] Mohammed A, Fadhil R, Mahmood MS, Al-Waeli HA. Diagnostic biomarkers for periodontitis (observational casecontrol study). J Baghdad Coll Dent 2024;36:11—9. https:// doi.org/10.26477/JBCD.V36I2.3673.

[20] Giannobile WV. Salivary diagnostics for periodontal diseases. J Am Dent Assoc 2012;143:6S—11S. https://doi.org/10. 14219/jada.archive.2012.0341.

[21] Bellagambi FG, Lomonaco T, Salvo P, Vivaldi F, Hangouet € M, Ghimenti S, et al. Saliva sampling: Methods and devices. An overview. TrAC, Trends Anal Chem 2020; 124:115781. https://doi.org/10.1016/j.trac.2019.115781.

[22] Malamud D. Saliva as a diagnostic fluid. Dent Clin North Am 2011;55:159—78. https://doi.org/10.1016/j.cden.2010.08.004.

[23] Salim IK, Diajil AR. Assessment of salivary immunoglobulin A, interleu-kin-6 and C-reactive protein in chronic kidney dis-ease patients on hemodialysis and on conservative treatment. J Baghdad Coll Dent 2022;34:62—73. https://doi. org/10.26477/JBCD.V34I2.3146.

[24] Jassim AZJ, Al Dhaher ZA, Allyan FM. Evaluation of alpha amylase and peroxidase in saliva of pregnant women. J Baghdad Coll Dent 2023;35:21—7. https://doi.org/10.26477/ JBCD.V35I3.3448.

[25] Talib MA, Ali BG, Al-Rubaee EA, Mahdy M. The Effect of titanium dioxide nanoparticles on the activity of salivary peroxidase in periodontitis patients. J Baghdad Coll Dent 2023;35:10—9. https://doi.org/10.26477/JBCD.V35I2.3393.

[26] Podzimek S, Vondrackova L, Duskova J, Janatova T, Broukal Z. Salivary markers for periodontal and general diseases. Dis Markers 2016;2016:1—8. https://doi.org/10. 1155/2016/9179632.

[27] Miller CS, King CP, Langub MC, Kryscio RJ, Thomas MV. Salivary biomarkers of existing periodontal disease. J Am Dent Assoc 2006;137:322—9. https://doi.org/10.14219/jada. archive.2006.0181.

[28] Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 2007;8(3):221—33. https://doi.org/10.1038/ nrm2125.

[29] Cui N, Hu M, Khalil RA. Biochemical and biological attributes of matrix metalloproteinases. Prog Mol Biol Transl Sci 2017;147:1. https://doi.org/10.1016/BS.PMBTS.2017.02.005.

[30] Elgezawi M, Haridy R, Almas K, Abdalla MA, Omar O, Abuohashish H, et al. Matrix metalloproteinases in dental and periodontal tissues and their current inhibitors: developmental, degradational and pathological aspects. Int J Mol Sci 2022;23. https://doi.org/10.3390/IJMS23168929.

[31] Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM. Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol 2000;18:1135—49. https://doi.org/ 10.1200/JCO.2000.18.5.1135.

[32] Sorsa T, Gursoy UK, Nwhator S, Hernandez M, Tervahartiala T, Leppilahti J, et al. Analysis of matrix metalloproteinases, especially MMP-8, in gingival creviclular fluid, mouthrinse and saliva for monitoring periodontal diseases. Periodontol 2000 2016;70:142—63. https://doi.org/ 10.1111/PRD.12101.

[33] Woessner JF, Taplin CJ. Purification and properties of a small latent matrix metalloproteinase of the rat uterus. J Biol Chem 1988;263:16918—25. 138 MA'AEN JOURNAL FOR MEDICAL SCIENCES 2025;4:132—139

[34] Wilson CL, Ouellette AJ, Satchell DP, Ayabe T, Lopez- Boado YS, Stratman JL, et al. Regulation of intestinal αdefensin activation by the metalloproteinase matrilysin in innate host defense. Science (1979) 1999;286:113—7. https:// doi.org/10.1126/SCIENCE.286.5437.113.

[35] Khuda F, Baharin B, Anuar NNM, Jayusman PA, Nasruddin SN. MMP-7, RANKL mRNA expression in the gingival tissue correlates with periodontitis: an in vivo study. Egypt Pharm J 2024;23:245—50. https://doi.org/10. 4103/epj.epj_147_23.

[36] Zeidan-Chuli a F, Yilmaz D, Hakkinen € L, Kon€ onen € E, Neves de Oliveira BH, Güncü G, et al. Matrix metalloproteinase-7 in periodontitis with type 2 diabetes mellitus. J Periodontal Res 2018;53:916—23. https://doi.org/10.1111/JRE.12583.

[37] Checchi V, Maravic T, Bellini P, Generali L, Consolo U, Breschi L, et al. The Role of Matrix Metalloproteinases in Periodontal Disease. Int J Environ Res Public Health 2020; 17:4923. https://doi.org/10.3390/IJERPH17144923.

[38] Lundmark A, Johannsen G, Eriksson K, Kats A, Jansson L, Tervahartiala T, et al. Mucin 4 and matrix metalloproteinase 7 as novel salivary biomarkers for periodontitis. J Clin Periodontol 2017;44:247—54. https://doi.org/10.1111/jcpe.12670.

[39] Chattopadhyay S, Arora R, Kishor A, Singh S, Alok A, Mitra M. MUC4 and MMP7 in saliva and gingival crevicular fluid (GCF) in adolescents at West Bengal, India. Bioinformation 2022;18:165—9. https://doi.org/10.6026/ 97320630018165.

[40] Emingil G, Tervahartiala T, Mantyl ~ a ~ P, Ma€att € a € M, Sorsa T, Atilla G. Gingival crevicular fluid matrix metalloproteinase (MMP)-7, extracellular MMP inducer, and tissue inhibitor of MMP-1 levels in periodontal disease. J Periodontol 2006;77: 2040—50. https://doi.org/10.1902/JOP.2006.060144.

[41] Dale BA, Kimball JR, Krisanaprakornkit S, Roberts F, Robinovitch M, O'Neal R, et al. Localized antimicrobial peptide expression in human gingiva. J Periodontal Res 2001; 36:285—94. https://doi.org/10.1034/j.1600-0765.2001.360503.x.

[42] Krisanaprakornkit S, Weinberg A, Perez CN, Dale BA. Expression of the peptide antibiotic human β-defensin 1 in cultured gingival epithelial cells and gingival tissue. Infect Immun 1998;66:4222—8. https://doi.org/10.1128/IAI.66.9. 4222-4228.1998.

[43] Mathews M, Jia HP, Guthmiller JM, Losh G, Graham S, Johnson GK, et al. Production of β-defensin antimicrobial peptides by the oral mucosa and salivary glands. Infect Immun 1999;67:2740. https://doi.org/10.1128/IAI.67.6.2740- 2745.1999.

[44] Yang D, Chertov O, Bykovskaia SN, Chen Q, Buffo MJ, Shogan J, et al. β-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science (1979) 1999; 286:525—8. https://doi.org/10.1126/SCIENCE.286.5439.525.

[45] Vardar-Sengul S, Demirci T, Sen BH, Erkizan V, Kurulgan E, Baylas H. Human β defensin-1 and -2 expression in the gingiva of patients with specific periodontal diseases. J Periodontal Res 2007;42:429—37. https://doi.org/ 10.1111/J.1600-0765.2006.00964.X.

[46] Schroeder BO, Wu Z, Nuding S, Groscurth S, Marcinowski M, Beisner J, et al. Reduction of disulphide bonds unmasks potent antimicrobial activity of human β 2- defensin 1. Nature 2011;469:419—23. https://doi.org/10.1038/ NATURE09674.

[47] Ko T-J, Byrd KM, Kim SA. The chairside periodontal diagnostic toolkit: past, present, and future. Diagnostics (Basel) 2021;11. https://doi.org/10.3390/diagnostics11060932.

[48] Al-Daragi FZ, Al-Ghurabi BH, Abdullah NN. Serum levels of antimicrobial peptides (Cathelicidins and Beta Defensins-1) in patients with periodontitis. J Baghdad Coll Dent 2024;36:9—18. https://doi.org/10.26477/JBCD.V36I1.3586.

[49] Rodrigues AE, Ribeiro A, Lourenço AG, Carolina A, Motta F, Komesu MC. Influence of periodontal condition on levels of human beta defensins 1 and 2 in saliva. J Microbiol Exp 2018;6. https://doi.org/10.15406/JMEN.2018.06.00186.

[50] Gürsoy UK, Gürsoy M, Liukkonen A, Suominen AL, Kon€ onen € E. Salivary human β-defensin 1-3 and human αdefensin-1 levels in relation to the extent of periodontal disease and tooth loss in the elderly. J Clin Med 2023;12:976. https://doi.org/10.3390/jcm12030976.

[51] Costa LCM, Soldati KR, Fonseca DC, Costa JE, Abreu MHNG, Costa FO, et al. Gingival crevicular fluid levels of human beta-defensin 1 in individuals with and without chronic periodontitis. J Periodontal Res 2018;53: 736—42. https://doi.org/10.1111/JRE.12558.

[52] Ansari Moghadam S, Pishadast S, Gholami L, Alijani E, Ansari Moghadam A, Hadilou M. Comparison of salivary beta-defensin-1 levels in patients with periodontitis before and after phase I periodontal therapy. J Adv Periodontol Implant Dent 2024;16:30—5. https://doi.org/10.34172/japid. 2024.002.

[53] Lu Q, Darveau RP, Samaranayake LP, Wang CY, Jin L. Differential modulation of human β-defensins expression in human gingival epithelia by Porphyromonas gingivalis lipopolysaccharide with tetra- and penta-acylated lipid A structures. Innate Immun 2009;15:325—35. https://doi.org/10. 1177/1753425909104899.

[54] Dale BA, Fredericks LP. Antimicrobial peptides in the oral environment: expression and function in health and disease. Curr Issues Mol Biol 2005;7:119—34.

[55] Yilmaz D, Topcu AO, Akcay EU, Altõndis M, Gursoy UK. Salivary human beta-defensins and cathelicidin levels in relation to periodontitis and type 2 diabetes mellitus. Acta Odontol Scand 2020;78:327—31. https://doi.org/10.1080/ 00016357.2020.1715471.

[56] Shao J, Zhang M, Wu L, Jia XW, Jin YH, Zeng XT. DEFB1 rs11362 polymorphism and risk of chronic periodontitis: a meta-analysis of unadjusted and adjusted data. Front Genet 2019;10:179. https://doi.org/10.3389/FGENE.2019. 00179.

[57] Hollingsworth MA, Swanson BJ. Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer 2004;4 (1):45—60. https://doi.org/10.1038/nrc1251.

[58] Chaturvedi P, Singh AP, Batra SK. Structure, evolution, and biology of the MUC4 mucin. FASEB J 2008;22:966—81. https://doi.org/10.1096/FJ.07-9673REV.

[59] Van Putten JPM, Strijbis K. Transmembrane mucins: signaling receptors at the intersection of inflammation and cancer. J Innate Immun 2017;9:281. https://doi.org/10.1159/ 000453594.

[60] Davanian H, Stranneheim H, Båge T, Lagervall M, Jansson L, Lundeberg J, et al. Gene expression profiles in paired gingival biopsies from periodontitis-affected and healthy tissues revealed by massively parallel sequencing. PLoS One 2012;7:e46440. https://doi.org/10.1371/JOURNAL. PONE.0046440.

[61] Relvas M, Mendes-Frias A, Gonçalves M, Salazar F, Lopez- Jarana P, Silvestre R, et al. Salivary IL-1β, IL-6, and IL-10 are key biomarkers of periodontitis severity. Int J Mol Sci 2024; 25. https://doi.org/10.3390/IJMS25158401.

[62] Imran NK, Abdulbaqi HR, Milward M. The prevalence of periodontitis in an Iraqi population using the 2017 classification. J Baghdad Coll Dent 2024;36:1—10. https://doi.org/10. 26477/JBCD.V36I2.3668.

[63] Sulijaya B, Masulili SLC, Auerkari EI. Human betadefensin-1 and periodontal disease: the past, present, and future. J Indones Dent Assoc 2021;4:61—8. https://doi.org/10. 32793/JIDA.V4I1.624

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