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ISSN : 1226-7155(Print)
ISSN : 2287-6618(Online)
International Journal of Oral Biology Vol.50 No.1 pp.8-16
DOI : https://doi.org/10.11620/IJOB.2025.50.1.8

Comparative approaches and insights into animal models of periodontitis

Jaemin Joun1,2, Zhao Wang1,2, Ju Han Song1,2*, Jeong-Tae Koh1,2*
1Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju 61186, Republic
of Korea
2Hard-tissue Biointerface Research Center, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea

†Jaemin Joun and Zhao Wang contributed equally to this work.


*Correspondence to: Ju Han Song, E-mail: juhan12@hanmail.nethttps://orcid.org/0000-0001-6049-3212
*Correspondence to: Jeong-Tae Koh, E-mail: jtkoh@chonnam.ac.krhttps://orcid.org/0000-0001-6279-6487
February 28, 2025 March 5, 2025

Abstract


Periodontitis is a chronic inflammatory disease characterized by the progressive destruction of periodontal tissue and alveolar bone loss. To develop effective treatment strategies, a model that mimics this disease must be implemented. From this perspective, animal models can be used to investigate its mechanisms by reproducing disease progression and providing insights into host-microbe interactions, immune responses, and bone remodeling. In addition, periodontitis-associated bone loss fundamentally differs from systemic bone loss. Targeted treatments require distinguishing periodontitis-induced and systemic bone loss mechanisms. This review examines the rationale for using animal models in periodontal research and evaluates various experimental approaches, such as bacterial inoculation, ligature-induced periodontitis, and chemically induced inflammation. These models have advanced our understanding of periodontal disease but have limitations in replicating the chronic nature of periodontitis and human immune responses. However, current models cannot fully replicate chronic disease progression and human immune responses. Recent developments have focused on improving animal models to more accurately simulate disease progression and host responses, which has led to the elucidation of the immunomodulatory mechanisms of periodontitis and their relevance to the human dental environment. Moreover, new approaches, such as developing age-related periodontitis models and improving ligature techniques, could enhance experimental reproducibility and translational potential. Future studies are needed to reflect these improvements and enhance the clinical relevance of periodontitis models.


Periodontitis , Animal models , Inflammation , Periodontium

초록

    © The Korean Academy of Oral Biology. All rights reserved.

    This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Introduction

    Periodontitis is a chronic inflammatory disease that affects the entire periodontium, including the gingiva, periodontal ligament, cementum, and alveolar bone. While both periodontitisassociated and systemic bone loss involves bone resorption, their underlying mechanisms differ significantly. Systemic bone loss is primarily influenced by estrogen deficiency, parathyroid hormone dysregulation, and reduced mechanical loading. Additionally, metabolic disorders such as diabetes contribute to bone loss by impairing bone remodeling and increasing osteoclastic activity [1].

    Unlike systemic bone loss, which is primarily influenced by metabolic and endocrine factors, periodontitis-induced de- struction of both soft and hard periodontal tissues is driven by a localized immune response to microbial dysbiosis [2,3]. Periodontal pathogens such as Porphyromonas gingivalis , Treponema denticola, and Tannerella forsythia elicit an excessive inflammatory response, leading to the upregulation of cytokines such as IL-1β, TNF-α, IL-6, and IL-17 [4,5]. This persistent pro-inflammatory state drives alveolar bone resorption while also impairing tissue regeneration, ultimately leading to progressive loss of tooth-supporting tissues. Among these pathological changes, alveolar bone loss is considered a hallmark of periodontitis and serves as a key diagnostic and prognostic indicator of disease severity.

    While significant progress has been made in understanding the molecular and cellular mechanisms of periodontitis, the complexity of host-microbe interactions and the inflammatory microenvironment pose challenges to the development of effective therapeutic strategies [6,7]. Human clinical studies provide valuable insights, but ethical and practical constraints limit experimental interventions in patients. Therefore, animal models serve as indispensable tools to study the pathogenesis of periodontitis and to evaluate potential treatments under controlled conditions [8]. These models allow researchers to study key aspects of periodontal disease, including immune responses, microbial interactions, and bone remodeling, which are essential for translating basic research into clinical applications.

    Several animal models have been developed to simulate periodontitis, each with unique advantages and limitations. Experimentally induced models, including bacterial inoculation, ligature-induced periodontitis, and chemical induction models, have been widely utilized to recapitulate various aspects of the disease [9,10]. However, the translational relevance of these models remains a subject of ongoing debate, as differences in anatomy, immune response, and microbiome composition between animals and humans may influence disease outcomes.

    This review explores the comparative advantages and limitations of various animal models used in periodontitis research. We examine their relevance in the study of periodontal tissue destruction, particularly alveolar bone loss, and discuss their utility in the evaluation of novel therapeutic approaches. In addition, we highlight the translational potential of these models and suggest refinements to improve their clinical applicability.

    The experimental procedures were conducted in accordance with the ethical guidelines of the Animal Care and Use Committee of Chonnam National University (approval number: CNU IACUC-YB-2023-12).

    Necessity of Animal Models in Periodontal Research

    Clinical research on periodontitis is limited by ethical constraints and patient variability, making controlled animal studies necessary [11]. In addition, clinical research relies on observational data, which makes it difficult to establish causal relationships or identify precise biological mechanisms [12].

    Animal models are used to overcome these problems in periodontitis. These models allow controlled studies of periodontitis progression and treatment. Unlike in vitro models performed at the cellular level, animal models can analyze host immune responses, microbial interactions, and bone remodeling on a broader scale [13]. Various models have been developed to target more specific research goals, including genetic, microbial, and drug-induced regeneration [14,15].

    Despite their advantages, animal models exhibit speciesspecific differences in oral microbiota, immune responses, and disease progression. Rodent models, which are commonly used, have the disadvantage that they do not fully mimic the human oral environment in terms of anatomy and microbiology. In addition, relatively large animals, such as dogs and pigs, are anatomically and immunologically like humans but are relatively expensive to maintain. It is important to choose the right model based on the degree of human simulation and cost and ethical considerations [16].

    Considerations When Choosing Animal Model for Periodontal Research

    As mentioned earlier, the choice of animal model determines how well the human periodontitis environment is simulated and how reproducible the study is. Various species are used for periodontitis studies, each with distinct anatomical, immunological, and microbiological characteristics influencing experimental outcomes (Table 1) [13,17-20].

    Rodents have a well-studied genetic material, which can be utilized to apply transgenic models to study periodontitis. However, the oral microbiota composition of rodents differs from that of humans, resulting in different microbial interactions and disease progression. In addition, species-specific inflammatory stimulus lead to bone remodeling mechanisms that are different from those of humans.

    Larger animals, such as dogs and pigs, resemble human periodontal structures more closely but present ethical and logistical challenges [20]. Nonhuman primates provide the highest translational relevance but are rarely used due to cost and ethical constraints [21].

    Disease induction methods vary in their ability to replicate key features of human periodontitis. Bacterial inoculation models mimic microbial dysbiosis, ligation-induced models rapidly induce alveolar bone loss, and chemically induced models allow targeted immune system stimulation. The model selection should align with study objectives, balancing disease progression speed with physiological accuracy [22].

    Reproducibility is a key factor in experimental validity. Standardized assessments, such as micro-computed tomography (μ-CT) and histological analysis, ensure consistent measurement of bone loss and inflammatory responses. Additionally, the translational potential must be considered; rodent models are best suited for mechanistic studies, while larger animals provide a better platform for biomaterial testing and regenerative research [23,24].

    Ethical considerations play a crucial role in model selection. Adherence to the 3Rs principle―Replacement by utilizing in vitro models when feasible, Reduction to ensure that the number of animals used is kept to a minimum, and Refinement by refining experimental protocols to reduce animal distress—ensures compliance with international animal welfare regulations and maintains the integrity of periodontal research [25].

    Induction Models for Periodontitis in Animals

    Animal induction allows host-microbe interactions, inflammatory responses, and bone resorption to be simulated to mimic the human dental environment. Depending on the research objectives, various induction methods simulate periodontitis, including bacterial inoculation, ligature placement, chemical induction [14].

    1. Bacterial inoculation models

    Bacterial inoculation models aim to replicate the role of pathogenic bacteria in periodontitis by introducing specific periodontal pathogens into the oral cavity of animals. Commonly used pathogens include P. gingivalis , Fusobacterium nucleatum, and T. forsythia, which disrupt periodontal homeostasis and induce host immune responses. These models provide a controlled platform for studying microbial interactions, immune responses, and the efficacy of antimicrobial treatments [26].

    The human microbiome transplantation model introduces human-derived subgingival biofilms into germ-free or antibiotic- treated mice to better replicate the dynamics of the human microbiome. Introducing human-derived microbes into animals can study human periodontal disease and host-microbe interactions under conditions that more closely resemble the human oral cavity. However, stable colonization and perfect mimicry of the human immune response are difficult to achieve. Research is underway to fine-tune bacterial load and host conditions to better mimic the human oral environment by controlling the efficiency of bacterial colonization to more closely resemble that of humans [27].

    2. Ligation-induced periodontitis models

    Ligation-induced periodontitis models are among the most used methods for inducing experimental periodontitis due to their ability to promote rapid plaque accumulation and biofilm formation, leading to localized inflammation and alveolar bone resorption. The placement of ligatures around teeth physically disrupts natural cleaning mechanisms. It facilitates bacterial colonization, making this model an effective tool for studying host-microbe interactions, immune responses, and therapeutic interventions [28].

    Various modifications of the ligature-induced periodontitis model have been developed to account for species-specific anatomical differences and improve experimental consistency. In large animal models, such as dogs and non-human primates, the traditional ligature technique involves securing silk or nylon ligatures around a single molar. This method effectively promotes plaque accumulation and local inflammation by preventing natural cleaning mechanisms, resembling human periodontal disease progression [29]. The anatomical structure of these animals allows for precise ligation, making them useful for studying long-term disease progression and evaluating regenerative therapies.

    A simplified ligature model has been introduced for small rodents. In this model, a dual-knotted silk ligature is positioned between two adjacent molars, reducing technical difficulties while maintaining reproducibility in inflammation induction and alveolar bone resorption. In existing studies, there are several methods of ligation placement, each with distinct advantages and disadvantages (Table 2) [28,30-33]. These methods differ slightly regarding the ligation’s stability, ability to induce inflammation, and potential for mechanical trauma.

    Tied loop ligature and dual-knotted ligature induce alveolar bone loss and inflammatory response in C57BL/6 mice (Fig. 1). According to the results reproduced by our group, both methods effectively induce periodontitis through μ-CT analysis and cementoenamel junction to alveolar bone crest measurements and promote osteoclast activation and inflammatory response. Although there were differences in the degree and distribution of alveolar bone loss depending on the ligature method, both ligature methods are helpful in periodontitis models. They are evaluated as inducing bone resorption and inflammatory responses.

    The ligature-induced model is advantageous due to its rapid and predictable induction of periodontitis. It allows reproducible assessments of inflammatory responses, osteoclast activation, and alveolar bone loss. Despite its widespread use, the ligature-induced model has inherent limitations. One primary concern is that the mechanical trauma caused by the ligature itself can contribute to periodontal tissue destruction independent of bacterial infection [34]. Furthermore, while this model successfully induces acute inflammation and alveolar bone loss within a short period, it does not fully mimic human periodontitis’ chronic and progressive nature [35].

    Recent studies have investigated nylon thread, stainless steel wire, to improve standardization and accuracy of disease modeling [36,37]. These alternative materials more effectively mimic the progression of chronic periodontitis by creating a sustained inflammatory environment. Introducing stainless steel wire and polymer-coated ligation methods in small rodent models has improved ligation stability, biofilm formation, and bacterial adhesion. This method allows for a more stable biofilm in rodents, resulting in a more consistent periodontitis environment. Furthermore, a new approach has been introduced using C+ nickel-titanium orthodontic wire, which has improved stability compared to silk ligatures to maintain bacterial colonization and thus prolong inflammation [36]. Studies have also investigated the impact of ligature placement on different tooth types, revealing that molar ligature models produce more consistent alveolar bone loss than incisor ligature models, making them a preferred choice for periodontitis research.

    In addition, the combination of ligature placement with bacterial inoculation has been explored to improve disease modeling. This dual approach replicates the complex interactions between host immunity and microbial dysbiosis over extended periods, making it a more suitable model for studying longterm periodontal disease mechanisms [38].

    3. Chemical induction models

    Chemical induction models utilize pro-inflammatory agents to initiate localized immune responses and alveolar bone resorption without direct microbial involvement. These models are beneficial for studying inflammatory signaling pathways and cytokine-mediated bone destruction.

    The trinitrobenzene sulfonic acid (TNBS) model induces periodontitis by acting as a hapten. This hapten modifies host proteins and elicits a strong T-cell-mediated immune response, which leads to extensive periodontal inflammation and tissue degradation [39].

    The dextran sulfate sodium (DSS) model induces periodontitis through epithelial barrier disruption, leading to increased immune cell infiltration and gingival inflammation [40]. This model is handy for investigating immune-driven mechanisms of periodontal tissue destruction, as it allows for studying inflammatory signaling pathways without direct bacterial stimulation. However, the lack of bacterial relevance in this model makes it difficult to fully mimic the complex disease environment, as the microbial imbalance of the intestinal flora plays an important role in human periodontitis.

    To overcome these limitations, research is being conducted on combining DSS treatment with bacterial inoculation. This can mimic host-microbial interactions in periodontitis and is helpful for treatment strategies targeting inflammation and microbial imbalance [35].

    Conclusion

    Animal models have been instrumental in advancing our understanding of periodontitis, particularly in elucidating the complex interactions between host immune responses, microbial dysbiosis, and bone remodeling. Using animal models in periodontitis research is essential for understanding alveolar bone loss and inflammatory mechanisms. This review analyzes the pathogenesis of periodontitis, the need for animal models, the advantages and disadvantages of each animal model, and periodontitis induction models, reflecting recent research trends. Various models have been developed as periodontitis induction models, including bacterial inoculation, ligation-induced periodontitis, and chemical-induced models, each with distinct advantages and limitations.

    Bacterial inoculation models allow for studying specific pathogenic microbes and their role in periodontal disease progression. This model closely mimics the microbial dysbiosis observed in human periodontitis. However, it needs to be standardized to mimic infection and disease phenomena like those in the human oral environment.

    On the other hand, the ligation-induced periodontitis model can cause a rapid and reproducible inflammatory response through physical destruction and is widely used to study alveolar bone loss and immune responses. Despite this utility, the question of whether mechanical trauma from ligation can influence disease progression independent of bacterial factors remains to be addressed.

    Chemical-induced models such as TNBS or DSS instillation are used to study inflammatory signaling pathways as they allow for targeted immune activation without direct bacterial instillation.

    Each model has contributed significantly to periodontal research, but no single approach fully encapsulates the chronic and progressive nature of periodontitis in humans. Therefore, multiple models can be used simultaneously to study disease pathology and treatment response.

    To further improve periodontitis models and their relevance to human disease, future research should focus on the following key areas: 1) integration of multi-factorial models, 2) longitudinal and aging models, and 3) humanized models for translational research. Integration of the multi-factorial Model is combining different model approaches. It may yield a more comprehensive representation of periodontitis pathogenesis via integrating mechanical, microbial, and host-specific factors to reflect the complexity of human periodontitis. Since periodontitis is a progressive disease, longitudinal studies that assess disease development over extended timeframes are needed. Additionally, age-related periodontitis models will provide valuable insights into the interplay between aging and periodontal disease. Humanized mouse models incorporating elements of the human immune system can help accurately test therapeutic drugs. These models can improve the translational potential of animal research by bridging the gap between preclinical research and human clinical trials.

    By solving these problems, future research can improve the accuracy of periodontitis models and further develop treatment strategies for patients with periodontal disease.

    Funding

    This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (no. NRF-2019R1A5A2027521); Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (no. NRF- 2020R1I1A1A01061824).

    Conflicts of Interest

    No potential conflict of interest relevant to this article was reported.

    Figure

    IJOB-50-1-8_F1.gif

    Micro-computed tomography (μ-CT) and cementoenamel junction to alveolar bone crest (CEJ-ABC) analysis of periodontitis models induced by tied loop and dual-knotted ligature. (A) Final placement of the tied loop ligature in the periodontitis model of mice. (B) Final placement of the dual-knotted ligature in the periodontitis model of mice. (C) Alveolar bone loss in C57BL/6 mice with tied loop ligature using μ-CT and CEJ-ABC analysis. μ-CT images and quantitative analysis results comparing alveolar bone loss in C57BL/6 mice after application of the tied loop ligature. The μ-CT images of C57BL/6 mice show alveolar bone resorption after ligature. The alveolar bone loss in the right and left buccal and lingual regions of the C57BL/6 mice was displayed to assess the pattern of periodontal tissue loss. The graph below measures the CEJ-ABC distance to quantify alveolar bone loss. The buccal and lingual regions of the right and left sides were analyzed in C57BL/6 mice, and the left sides were used as control. All experiments were conducted in triplicate (n = 3) to ensure reproducibility. (D) Alveolar bone loss in C57BL/6 mice with dual-knotted ligatures using μ-CT and CEJ-ABC analysis. μ-CT images and quantitative analysis results comparing alveolar bone loss in C57BL/6 mice with dual-knotted ligatures. The μ-CT images taken after applying dual-knotted ligature on a C57BL/6 mice show the pattern of alveolar bone loss in the right and left buccal and lingual regions. In the graph below, CEJ-ABC was measured to quantify alveolar bone loss. The right and left buccal and lingual areas of C57BL/6 mice were analyzed, and the left sides were used as control. All experiments were conducted in triplicate (n = 3) to ensure reproducibility.

    *p < 0.05, **p < 0.01, ***p < 0.001 vs. control.

    Table

    Animal models for periodontal research

    This table summarizes the commonly used animal species and provides each model’s advantages, limitations, and main applications in periodontal research.

    Ligature types in periodontitis models

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