CALPROTECTIN AS AN EMERGING INFLAMMATORY BIOMARKER IN PERIODONTITIS: A SYSTEMATIC REVIEW
Abstract
Background: Calprotectin is a neutrophil-derived inflammatory protein implicated in several chronic inflammatory diseases, including periodontitis. Its potential role as a biomarker for periodontal disease has gained increasing attention.
Aim: To systematically review the available evidence on the association between calprotectin and periodontal disease and evaluate its diagnostic and therapeutic significance.
Methods: A systematic search of PubMed, Scopus, Web of Science, and Google Scholar was conducted according to PRISMA guidelines. Fourteen human studies published between January 2016 and May 2026 assessing calprotectin levels in saliva, gingival crevicular fluid (GCF), serum, or blood in relation to periodontal disease was included.
Results: All included studies reported elevated calprotectin levels in periodontitis patients compared with healthy controls. Calprotectin concentration increased in periodontitis and showed positive correlations with clinical periodontal parameters, including probing pocket depth, clinical attachment loss, and bleeding on probing. Salivary calprotectin demonstrated good diagnostic performance, with reported ROC/AUC values ranging from 0.86 to 0.894. Additionally, calprotectin levels were associated with key periodontal pathogens and were significantly reduced following nonsurgical periodontal therapy in most intervention studies.
Conclusion: Current evidence suggests that calprotectin is a promising biomarker for the diagnosis, assessment of disease severity, and monitoring of treatment outcomes in periodontal disease.
Keywords:
Calprotectin, Periodontitis, Biomarker, Saliva, Gingival Crevicular Fluid
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References
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9. Khaki-Khatibi F, Qujeq D, Kashifard M, Moein S, Maniati M, Vaghari-Tabari M. Calprotectin in inflammatory bowel disease. Clin Chim Acta. 2020 Nov;510:556-565. doi: 10.1016/j.cca.2020.08.025. Epub 2020 Aug 18. PMID: 32818491; PMCID: PMC7431395.
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11. Ometto F, Friso L, Astorri D, Botsios C, Raffeiner B, Punzi L, Doria A. Calprotectin in rheumatic diseases. Exp Biol Med (Maywood). 2017 Apr;242(8):859-873. doi: 10.1177/1535370216681551. Epub 2016 Jan 1. PMID: 27895095; PMCID: PMC5407536.
12. Kamatham SA, Chava VK. Comparison of salivary calprotectin levels in periodontitis associated with diabetes mellitus after low-level laser therapy as an adjunct to scaling and root planing: A randomized clinical trial. J Indian Soc Periodontol. 2022 Mar-Apr;26(2):143-150. doi: 10.4103/jisp.jisp_149_21. Epub 2022 Mar 1. PMID: 35321295; PMCID: PMC8936012.
13. Li B, Li G, Song Z, Zhang Z. Serum Calprotectin as a Promising Inflammatory Biomarker in Psoriatic Arthritis: a 1-Year Longitudinal Study. Rheumatol Ther. 2023 Feb;10(1):149-160. doi: 10.1007/s40744-022-00501-5. Epub 2022 Oct 21. PMID: 36271188; PMCID: PMC9931953
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15. Kido J., Nishikawa S., Ishida H., et al. Identification of calprotectin, a calcium binding leukocyte protein, in human dental calculus matrix. Journal of Periodontal Research. 1997;32(4):355–361. doi: 10.1111/j.1600-0765.1997.tb00545.x. [DOI] [PubMed] [Google Scholar]
16. Miyasaki K. T., Voganatsi A., Huynh T., Marcus M., Underwood S. Calprotectin and lactoferrin levels in the gingival crevicular fluid of children. Journal of Periodontology. 1998;69(8):879–883. doi: 10.1902/jop.1998.69.8.879. [DOI] [PubMed] [Google Scholar]
17. Kojima T., Andersen E., Sanchez J. C., et al. Human gingival crevicular fluid contains MRP8 (S100A8) and MRP14 (S100A9), two calcium-binding proteins of the S100 family. Journal of Dental Research. 2000;79(2):740–747. doi: 10.1177/00220345000790020701. [DOI] [PubMed] [Google Scholar]
18. Kido J.-i., Nakamura T., Kido R., et al. Calprotectin, a leukocyte protein related to inflammation, in gingival crevicular fluid. Journal of Periodontal Research. 1998;33(7):434–437. doi: 10.1111/j.1600-0765.1998.tb02340.x. [DOI] [PubMed] [Google Scholar]
19. Kido J., Nakamura T., Kido R., et al. Calprotectin in gingival crevicular fluid correlates with clinical and biochemical markers of periodontal disease. Journal of Clinical Periodontology. 1999;26(10):653–657. doi: 10.1034/j.1600-051X.1999.261004.x. [DOI] [PubMed] [Google Scholar]
20. Nakamura T., Kido J., Kido R., et al. The association of calprotectin level in gingival crevicular fluid with gingival index and the activities of collagenase and aspartate aminotransferase in adult periodontitis patients. Journal of Periodontology. 2000;71(3):361–367. doi: 10.1902/jop.2000.71.3.361. [DOI] [PubMed] [Google Scholar]
21. Lundy F. T., Chalk R., Lamey P. J., Shaw C., Linden G. J. Quantitative analysis of MRP-8 in gingival crevicular fluid in periodontal health and disease using microbore HPLC. Journal of Clinical Periodontology. 2001;28(12):1172–1177. doi: 10.1034/j.1600-051X.2001.281213.x. [DOI] [PubMed] [Google Scholar]
22. Haririan, H., Andrukhov, O., Pablik, E., Neuhofer, M., Moritz, A. and Rausch-Fan, X. (2016), Comparative Analysis of Calcium-Binding Myeloid-Related Protein-8/14 in Saliva and Serum of Patients With Periodontitis and Healthy Individuals. Journal of Periodontology, 87: 184-192. https://doi.org/10.1902/jop.2015.150254
23. Lira-Junior R, Ozturk VO, Emingil G, et al. Salivary and serum markers related to innate immunity in generalized aggressive periodontitis. J Periodontol 2017;88(12):1339–1347. DOI: 10.1902/ jop.2017.170287
24. Kajiura Y, Lew JH, Ikuta T, et al. Clinical significance of GCF sIL-6R and calprotectin to evaluate the periodontal inflammation. Ann Clin Biochem 2017;54(6):664–670. DOI: 10.1177/0004563216680232
25. Shin MS, Kim YG, Shin YJ, et al. Deep sequencing salivary proteins for periodontitis using proteomics. Clin Oral Investig 2019;23(9):3571– 3580. DOI: 10.1007/s00784-018-2779-1
26. Holmstrom SB, Lira-Junior R, Zwicker S, et al. MMP-12 and S100s in saliva reflect different aspects of periodontal inflammation. Cytokine 2019;113:155–161. DOI: 10.1016/j.cyto.2018.06.036
27. Karna S, Shin YJ, Kim S, et al. Salivary S100 proteins screen periodontitis among Korean adults. J Clin Periodontol 2019;46(2):181–188. DOI: 10.1111/jcpe.13059
28. Nemec M, Mittinger N, Bertl M, Liu E, Jonke E, Andrukhov O, Rausch-Fan X. Salivary MRP-8/14 and the presence of periodontitis-associated bacteria in children with bonded maxillary expansion treatment. Clin Oral Investig. 2021 Jun;25(6):3767-3774. doi: 10.1007/s00784-020-03706-6. Epub 2020 Dec 3. PMID: 33270150; PMCID: PMC8137619.
29. Kim HD, Karna S, Shin Y, Vu H, Cho HJ, Kim S. S100A8 and S100A9 in saliva, blood and gingival crevicular fluid for screening established periodontitis: a cross-sectional study. BMC Oral Health. 2021 Aug 9;21(1):388. doi: 10.1186/s12903-021-01749-z. PMID: 34372836; PMCID: PMC8351418.
30. Aadhithiyan, Ravishankar PL, Kalaivani V, Jishnavi Priya P, Trilochansai GV, Dolly S. Estimation of calprotectin and osteopontin levels in the gingival crevicular fluid and serum of aggressive periodontitis patients before and after scaling and root planing: a clinical and biochemical study. Journal of Clinical Otorhinolaryngology, Head and Neck Surgery. 2023;27(2):1626-1635.
31. Menon P, Puzhankara L, Venugopal A, Ramachandran S. A Comparative Study on Calprotectin Concentration in Periodontitis Patients Before and After Non-surgical Periodontal Therapy. Cureus. 2025 Jan 30;17(1):e78221. doi: 10.7759/cureus.78221. PMID: 40026958; PMCID: PMC11871526.
32. Popoca-Hernández EA, Martínez-Martínez RE, González-Amaro RF, Niño-Moreno PDC, Ayala-Herrera JL, Jerezano-Domínguez AV, Espinosa-Cristóbal LF, Márquez-Corona ML, Espinosa-de Santillana IA, Medina-Solís CE. Impact of Non-Surgical Periodontal Treatment on the Concentration and Level of MRP-8/14 (Calprotectin) as an Inflammatory Biomarker in Women with Periodontitis and Rheumatoid Arthritis: A Quasi-Experimental Study. Diseases. 2024 Jan 1;12(1):12. doi: 10.3390/diseases12010012. PMID: 38248363; PMCID: PMC10814914.
33. Bayırlı AB, Uytun M, Türkiş FC, Saruhan E, Keceli HG. Salivary Biomarker Profile in Periodontal Diseases: A Cross-Sectional Study on Leptin, Adiponectin, and Calprotectin. Diagnostics (Basel). 2025 Nov 7;15(22):2822. doi: 10.3390/diagnostics15222822. PMID: 41300847; PMCID: PMC12651924.
34. George AK, Malaiappan S, Narayan V, Jayaraman S, Suresh N. Short-term effects of non-surgical periodontal therapy on oral fluid calprotectin levels in stages III or IV periodontitis: a longitudinal observational study. J Clin Diagn Res. 2025;19(12):ZC12-ZC16. doi:10.7860/JCDR/2025/81344.22077
35. Kido JI, Kido R, Ando S, Shinozaki A, Bando M, Inagaki Y, Seki Y, Ohiro Y, Yumoto H. Evaluation of salivary calprotectin as a marker for screening periodontitis using a latex agglutination turbidimetric immunoassay system: a cross-sectional study. BMC Oral Health. 2026 Jan 7;26(1):240. doi: 10.1186/s12903-025-07622-7. PMID: 41501804; PMCID: PMC12870218.
2. Verma K, Singh A. Biomarkers in periodontal health and diseases [Internet]. IP Int J Periodontol Implantol. 2024 [cited 2026 Jun 05];9(2):64-67.
3. Stríz I, Trebichavský I. Calprotectin - a pleiotropic molecule in acute and chronic inflammation. Physiol Res 2004;53(3):245–253. PMID: 15209531.
4. Nishikawa Y, Kajiura Y, Lew JH, et al. Calprotectin induces IL-6 and MCP-1 production via toll-like receptor 4 signaling in human gingival fibroblasts. J Cell Physiol 2017;232(7):1862–1871. DOI: 10.1002/jcp.25724
5. Wei L, Liu M, Xiong H. Role of calprotectin as a biomarker in periodontal disease. Mediators Inflamm 2019;2019:3515026. DOI: 10.1155/2019/3515026
6. Becerik S, Afacan B, Oztürk VÖ, et al. Gingival crevicular fluid calprotectin, osteocalcin and cross-linked N-terminal telopeptid levels in health and different periodontal diseases. Dis Markers 2011;31(6):343–352. DOI: 10.3233/DMA-2011-0849
7. Booth A, Clarke M, Dooley G, Ghersi D, Moher D, Petticrew M, Stewart L. The nuts and bolts of PROSPERO: an international prospective register of systematic reviews. Syst Rev. 2012 Feb 9;1:2. doi: 10.1186/2046-4053-1-2. PMID: 22587842; PMCID: PMC3348673.
8. Gualdi-Russo E, Zaccagni L. The Newcastle–Ottawa Scale for Assessing the Quality of Studies in Systematic Reviews. Publications. 2026; 14(1):4. https://doi.org/10.3390/publications14010004
9. Khaki-Khatibi F, Qujeq D, Kashifard M, Moein S, Maniati M, Vaghari-Tabari M. Calprotectin in inflammatory bowel disease. Clin Chim Acta. 2020 Nov;510:556-565. doi: 10.1016/j.cca.2020.08.025. Epub 2020 Aug 18. PMID: 32818491; PMCID: PMC7431395.
10. Kotsiou OS, Papagiannis D, Papadopoulou R, Gourgoulianis KI. Calprotectin in Lung Diseases. Int J Mol Sci. 2021 Feb 8;22(4):1706. doi: 10.3390/ijms22041706. PMID: 33567747; PMCID: PMC7915440.
11. Ometto F, Friso L, Astorri D, Botsios C, Raffeiner B, Punzi L, Doria A. Calprotectin in rheumatic diseases. Exp Biol Med (Maywood). 2017 Apr;242(8):859-873. doi: 10.1177/1535370216681551. Epub 2016 Jan 1. PMID: 27895095; PMCID: PMC5407536.
12. Kamatham SA, Chava VK. Comparison of salivary calprotectin levels in periodontitis associated with diabetes mellitus after low-level laser therapy as an adjunct to scaling and root planing: A randomized clinical trial. J Indian Soc Periodontol. 2022 Mar-Apr;26(2):143-150. doi: 10.4103/jisp.jisp_149_21. Epub 2022 Mar 1. PMID: 35321295; PMCID: PMC8936012.
13. Li B, Li G, Song Z, Zhang Z. Serum Calprotectin as a Promising Inflammatory Biomarker in Psoriatic Arthritis: a 1-Year Longitudinal Study. Rheumatol Ther. 2023 Feb;10(1):149-160. doi: 10.1007/s40744-022-00501-5. Epub 2022 Oct 21. PMID: 36271188; PMCID: PMC9931953
14. Cochran D. L. Inflammation and bone loss in periodontal disease. Journal of Periodontology. 2008;79(8s):1569–1576. doi: 10.1902/jop.2008.080233. [DOI] [PubMed] [Google Scholar]
15. Kido J., Nishikawa S., Ishida H., et al. Identification of calprotectin, a calcium binding leukocyte protein, in human dental calculus matrix. Journal of Periodontal Research. 1997;32(4):355–361. doi: 10.1111/j.1600-0765.1997.tb00545.x. [DOI] [PubMed] [Google Scholar]
16. Miyasaki K. T., Voganatsi A., Huynh T., Marcus M., Underwood S. Calprotectin and lactoferrin levels in the gingival crevicular fluid of children. Journal of Periodontology. 1998;69(8):879–883. doi: 10.1902/jop.1998.69.8.879. [DOI] [PubMed] [Google Scholar]
17. Kojima T., Andersen E., Sanchez J. C., et al. Human gingival crevicular fluid contains MRP8 (S100A8) and MRP14 (S100A9), two calcium-binding proteins of the S100 family. Journal of Dental Research. 2000;79(2):740–747. doi: 10.1177/00220345000790020701. [DOI] [PubMed] [Google Scholar]
18. Kido J.-i., Nakamura T., Kido R., et al. Calprotectin, a leukocyte protein related to inflammation, in gingival crevicular fluid. Journal of Periodontal Research. 1998;33(7):434–437. doi: 10.1111/j.1600-0765.1998.tb02340.x. [DOI] [PubMed] [Google Scholar]
19. Kido J., Nakamura T., Kido R., et al. Calprotectin in gingival crevicular fluid correlates with clinical and biochemical markers of periodontal disease. Journal of Clinical Periodontology. 1999;26(10):653–657. doi: 10.1034/j.1600-051X.1999.261004.x. [DOI] [PubMed] [Google Scholar]
20. Nakamura T., Kido J., Kido R., et al. The association of calprotectin level in gingival crevicular fluid with gingival index and the activities of collagenase and aspartate aminotransferase in adult periodontitis patients. Journal of Periodontology. 2000;71(3):361–367. doi: 10.1902/jop.2000.71.3.361. [DOI] [PubMed] [Google Scholar]
21. Lundy F. T., Chalk R., Lamey P. J., Shaw C., Linden G. J. Quantitative analysis of MRP-8 in gingival crevicular fluid in periodontal health and disease using microbore HPLC. Journal of Clinical Periodontology. 2001;28(12):1172–1177. doi: 10.1034/j.1600-051X.2001.281213.x. [DOI] [PubMed] [Google Scholar]
22. Haririan, H., Andrukhov, O., Pablik, E., Neuhofer, M., Moritz, A. and Rausch-Fan, X. (2016), Comparative Analysis of Calcium-Binding Myeloid-Related Protein-8/14 in Saliva and Serum of Patients With Periodontitis and Healthy Individuals. Journal of Periodontology, 87: 184-192. https://doi.org/10.1902/jop.2015.150254
23. Lira-Junior R, Ozturk VO, Emingil G, et al. Salivary and serum markers related to innate immunity in generalized aggressive periodontitis. J Periodontol 2017;88(12):1339–1347. DOI: 10.1902/ jop.2017.170287
24. Kajiura Y, Lew JH, Ikuta T, et al. Clinical significance of GCF sIL-6R and calprotectin to evaluate the periodontal inflammation. Ann Clin Biochem 2017;54(6):664–670. DOI: 10.1177/0004563216680232
25. Shin MS, Kim YG, Shin YJ, et al. Deep sequencing salivary proteins for periodontitis using proteomics. Clin Oral Investig 2019;23(9):3571– 3580. DOI: 10.1007/s00784-018-2779-1
26. Holmstrom SB, Lira-Junior R, Zwicker S, et al. MMP-12 and S100s in saliva reflect different aspects of periodontal inflammation. Cytokine 2019;113:155–161. DOI: 10.1016/j.cyto.2018.06.036
27. Karna S, Shin YJ, Kim S, et al. Salivary S100 proteins screen periodontitis among Korean adults. J Clin Periodontol 2019;46(2):181–188. DOI: 10.1111/jcpe.13059
28. Nemec M, Mittinger N, Bertl M, Liu E, Jonke E, Andrukhov O, Rausch-Fan X. Salivary MRP-8/14 and the presence of periodontitis-associated bacteria in children with bonded maxillary expansion treatment. Clin Oral Investig. 2021 Jun;25(6):3767-3774. doi: 10.1007/s00784-020-03706-6. Epub 2020 Dec 3. PMID: 33270150; PMCID: PMC8137619.
29. Kim HD, Karna S, Shin Y, Vu H, Cho HJ, Kim S. S100A8 and S100A9 in saliva, blood and gingival crevicular fluid for screening established periodontitis: a cross-sectional study. BMC Oral Health. 2021 Aug 9;21(1):388. doi: 10.1186/s12903-021-01749-z. PMID: 34372836; PMCID: PMC8351418.
30. Aadhithiyan, Ravishankar PL, Kalaivani V, Jishnavi Priya P, Trilochansai GV, Dolly S. Estimation of calprotectin and osteopontin levels in the gingival crevicular fluid and serum of aggressive periodontitis patients before and after scaling and root planing: a clinical and biochemical study. Journal of Clinical Otorhinolaryngology, Head and Neck Surgery. 2023;27(2):1626-1635.
31. Menon P, Puzhankara L, Venugopal A, Ramachandran S. A Comparative Study on Calprotectin Concentration in Periodontitis Patients Before and After Non-surgical Periodontal Therapy. Cureus. 2025 Jan 30;17(1):e78221. doi: 10.7759/cureus.78221. PMID: 40026958; PMCID: PMC11871526.
32. Popoca-Hernández EA, Martínez-Martínez RE, González-Amaro RF, Niño-Moreno PDC, Ayala-Herrera JL, Jerezano-Domínguez AV, Espinosa-Cristóbal LF, Márquez-Corona ML, Espinosa-de Santillana IA, Medina-Solís CE. Impact of Non-Surgical Periodontal Treatment on the Concentration and Level of MRP-8/14 (Calprotectin) as an Inflammatory Biomarker in Women with Periodontitis and Rheumatoid Arthritis: A Quasi-Experimental Study. Diseases. 2024 Jan 1;12(1):12. doi: 10.3390/diseases12010012. PMID: 38248363; PMCID: PMC10814914.
33. Bayırlı AB, Uytun M, Türkiş FC, Saruhan E, Keceli HG. Salivary Biomarker Profile in Periodontal Diseases: A Cross-Sectional Study on Leptin, Adiponectin, and Calprotectin. Diagnostics (Basel). 2025 Nov 7;15(22):2822. doi: 10.3390/diagnostics15222822. PMID: 41300847; PMCID: PMC12651924.
34. George AK, Malaiappan S, Narayan V, Jayaraman S, Suresh N. Short-term effects of non-surgical periodontal therapy on oral fluid calprotectin levels in stages III or IV periodontitis: a longitudinal observational study. J Clin Diagn Res. 2025;19(12):ZC12-ZC16. doi:10.7860/JCDR/2025/81344.22077
35. Kido JI, Kido R, Ando S, Shinozaki A, Bando M, Inagaki Y, Seki Y, Ohiro Y, Yumoto H. Evaluation of salivary calprotectin as a marker for screening periodontitis using a latex agglutination turbidimetric immunoassay system: a cross-sectional study. BMC Oral Health. 2026 Jan 7;26(1):240. doi: 10.1186/s12903-025-07622-7. PMID: 41501804; PMCID: PMC12870218.
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15/06/2026
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Penumaka, R., N. B. Surabhi, M. Mupaneni, J. Chadalvada, D. Anumala, and H. S. Cherukula. “CALPROTECTIN AS AN EMERGING INFLAMMATORY BIOMARKER IN PERIODONTITIS: A SYSTEMATIC REVIEW ”. International Journal of Health Care and Biological Sciences, Vol. 7, no. 2, June 2026, pp. 29-36, doi:10.46795/ijhcbs.v7i2.900.
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