Animal models of idiopathic/progressive condylar resorption: a scoping review

Introduction

The Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) categorizes TMD as a pain-related disorder, an intra-articular disorder and osteoarthritis (OA) (1). A pain-related disorder includes masticatory muscle disorders and arthralgia. An intra-articular disorder includes disc displacement with or without reduction and limitation of mouth opening. A large population study found that 5% and 15% of the population experienced tenderness of the temporomandibular joint (TMJ) and masticatory muscles, respectively (2). The most prevalent diagnoses of TMD were found to be degenerative joint disease (33.0%) and disc displacement with reduction (33.0%) (3).

Although TMD are a well-known disease in craniofacial regions, TMD have complex and sometimes controversial etiologies. Furthermore, in analogous circumstances, deterioration of the TMJ may be observed in one patient, whereas it is not observed in another. Once degenerative changes commence in the TMJ, however, this pathology can be debilitating, resulting in a range of structural and functional abnormalities (4).

TMJOA, a degenerative joint disease, is known as the end stage of TMD, and most TMJOA patients exhibit joint pain as a main symptom. TMJOA is also a multifactorial disease, characterized by the breakdown of articular cartilage leading to joint destruction (5). Increased joint friction in the TMJ and functional overloading are recognized as the causes of degradation and subsequent abrasion of the TMJ components, thus instigating the onset and progression of TMJOA (6-8).

Until now, to fully explore the mechanism of TMD onset and progression and to develop its medications and treatment devices, many animal models of the diseases have been developed and adopted by many researchers. However, the development of animal models of idiopathic/progressive condylar resorption (ICR/PCR) is ongoing.

ICR/PCR is a unique TMJ condition that differs fundamentally from TMJOA. It primarily affects teenage and young adult women—by a striking margin of roughly 9:1 compared to males, whereas TMJOA typically emerges later in life and shows a more balanced sex distribution (9). Unlike OA, which is marked by joint inflammation—sclerosis, osteophytes, subchondral cysts, pain, and synovitis—ICR/PCR shows true bone loss in the mandibular condyle without signs of inflammation or joint effusion (10). The absence of these inflammatory and structural hallmarks makes ICR/PCR distinct. This distinct pathogenesis and non-inflammatory pathology underscore ICR/PCR as a clearly separate clinical entity from TMJOA.

In this paper, some basic concepts in the development of ICR/PCR animal models will be reviewed. The present article was composed of three parts. Part I will review the etiology of TMD. Part 2 will present the TMD animal models for each etiology of TMD. Finally, in Part 3, the possibility of development of ICR/PCR animal model will be discussed.

Etiology of TMD

There are numerous factors that can contribute to the development of TMD. The stomatognathic apparatus is usually unaffected by common oral parafunctional habits, such as bruxism, diurnal clenching, and thumb sucking (11,12). Sleep bruxism, which involves repetitive activity of the jaw muscles during sleep, may be associated with myofascial pain and arthralgia (11,13). Karibe et al. (14) demonstrated that damage to the teeth, jaw muscles, and TMJ may be caused by activity in excess of the individual resistance threshold or the host adaptive capacity being diminished (14). Several researchers have suggested that oral parafunctional habits are a possible cause of TMD in growing populations (14-16). Furthermore, bad posture or sleeping in a face down position are examples of postural habits that are also thought to be indicative of a potential TMD (11,17,18).

Etiological factors leading to disc displacement are considerably attributed to abnormal mechanical stresses in the mandibular condyles. Many risk factors for TMJ disc displacement were reported: chronic or acute injuries, deficient joint lubrication, specific occlusal irregularities, hyperactive lateral pterygoid muscles, joint hypermobility, and weakness or laxity in the TMJ ligaments and the joint capsule (5,19). We looked into the impact of overactivity of the lateral pterygoid muscle on the TMJ disc by using finite element models of the TMJ. We suggested that, in symptomatic joints where the disc is displaced anteriorly during prolonged clenching, it was located more posteriorly than in the healthy joints (20). This indicates that the development of the disc displacement may be linked to the hyperactivity of the lateral pterygoid muscle. The impact of oral parafunctions on disc displacement has also been considered. Furthermore, several human studies suggested that there is a significant link between daytime clenching and disc displacement (21,22). Nevertheless, there is still not sufficient evidence, and the definite etiology of disc displacement is still unknown.

The cause of TMJOA is complex and multifactorial, which makes it difficult to treat. Arnett et al. (23,24) reported a possible explanation for the degenerative changes in the TMJ resulting from dysfunctional articular remodeling due to a decreased adaptive capacity of the articulating surfaces and/or excessive or abnormal stress to the articular structures exceeding their normal adaptive capacity. The former is linked to the host adaptive capacity factors. The host adaptive capacity of the TMJ can be influenced by aging, systemic illness and hormonal conditions. Even when TMJ stresses are within an ordinary physiological range, these factors may be contributors to dysfunctional remodeling of the TMJ.

Mechanical factors may also lead to alterations to the structure of the TMJ (5,25). Notwithstanding the host adaptive capacity, excessive or imbalanced mechanical stimulations of the TMJ can lead to overloading of joint tissues, leading to the development and advancement of TMJOA. Furthermore, excessive or imbalanced joint stimulation may also induce anterior disc displacement. We investigated the impact of unilateral disc displacement on TMJ stress during prolonged clenching using a finite element model of the TMJ and it was suggested that a unilateral disc displacement might have an effect on the stresses in the unaffected joint during clenching, leading to the progression of the TMJOA (25). Recently, Kita et al. (26) investigated the effects of anterior disc displacement on TMJ using rat models with anteriorly displaced disc. This study reported morphological changes of mandibular condyle and histological changes throughout the TMJ and showed that anterior disc displacement could induce TMJOA even with less or minimal stress on the TMJ. A review of the mechanical causes of disc displacement and TMJOA suggests that trauma, parafunction, unstable occlusion, functional overloading, and increased joint friction are all deemed to exert a pivotal influence on onset of disc displacement and degradation of the condyle (8,23,24,27). These factors may occur alone, or they may be interrelated and/or interdependent. Morphological change is more likely to occur when two or more factors coexist (23). We present this article in accordance with the PRISMA-ScR reporting checklist (available at https://fomm.amegroups.com/article/view/10.21037/fomm-25-12/rc).

Methods

Search strategy

We searched PubMed and Scopus to retrieve relevant articles published between January 2000 and March 2025. To guarantee that our review covers both recent developments in ICR/PCR modeling and current research, we restricted our review to literature published between 2000 and 2025.

The following keywords were adopted: ‘temporomandibular joint’, ‘animal model’ and ‘condylar resorption’. We also searched for key references from the bibliographies of the relevant studies for key references. The search was updated in April 2025. The detailed search strategy, including concepts, keywords, and MeSH terms, is provided in Appendix 1. This scoping review was registered in the Open Science Framework. The registration link is as follows: https://osf.io/xqwc6.

Study selection

We included articles that met the following criteria: they were original or review articles that employed in vivo animal models to investigate the pathophysiology, progression, histology, or imaging characteristics of ICR or similar TMJ degenerative conditions. Only English-language studies with available full text were considered. The timeframe for publication was between January 2000 to March 2025. The extracted data included: publication details including authors, publication year, and journal; animal model characteristics including species, sex, and age; model induction method including mechanical loading, surgical alteration, and so on; study objective and outcome measures including histological, histometrical, and radiographic; and main findings including summary of reported TMJ changes. We excluded studies that did not involve animal models (e.g., human-only, in vitro, or computer-generated analyses), as well as those focused on unrelated TMJ disorders such as ankylosis, arthritis without resorption, or trauma-only models.

Relevant publications were retrieved from the reference lists and analyzed further to determine whether they met the inclusion criteria. Data retrieval and extraction were performed by the authors. The standard of the retrieved articles was not explained. Figure 1 delineates the number of records that were identified and eliminated from the searched database.

Figure 1 PRISMA flowchart. ICR, idiopathic condylar resorption; PCR, progressive condylar resorption; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Results

Search results

A total of 37 articles were extracted from the titles and abstracts of all evaluated databases using the search strategy. After reviewing the abstracts, 17 articles were excluded. The remaining 20 studies were then examined separately for eligibility by three authors (E.T., Y.W., and A.S.R.). Ultimately, seven articles satisfied the inclusion criteria. These were then processed for critical evaluation (Table 1) summarizes the development of ICR/PCR animal models.

Development of ICR/PCR animal model

ICR/PCR is characterized by the specific and progressive resorption of the mandibular condyle, which leads to a significant reduction in the height of the mandibular ramus (35). Growing evidence suggests that excessive and/or abnormal loading resulting in microtrauma is essential for the onset and development of TMJOA. However, different from TMJOA, ICR/PCR is an aggressive but non-inflammatory form of joint degradation, which is usually less pain (36). Since ICR/PCR has been reported to develop most commonly in teenage girls and postmenopausal women with a sex ratio of 1:9 to 1:16 (37), female hormone is considered as a crucial factor of ICR/PCR. Gunson et al. (38) reported that decreased blood concentrations of 17β-estradiol are a major cause of ICR/PCR. Milam et al. (39) also reported that estrogen receptors are abundant in the TMJ of females, and that these receptors themselves may cause condylar resorption and deformity, including ICR. However, women with a lack of female hormone do not always show severe condylar resorption, and most women show a healthy mandibular condyle even under a deficient condition of the female hormone.

Several researchers have proposed the hypothesis that degenerative illnesses of the TMJ, including ICR/PCR and TMJOA, are the outcome of a combination of etiological factors, including imbalances in sex-hormones and excessive mechanical stress (28,29). Ootake et al. (28) investigated the effect of TMJ overloading and sex hormone deficiency on degradative condylar alterations in orchiectomized (ORX) or ovariectomized (OVX) mice. Their findings indicated that overloads to the TMJ exacerbate condylar collapse in OVX and ORX mice. It was also reported by Wu et al. (29) that the most severe condylar destruction was exhibited by OVX mice with increased occlusal height. This suggests that having no or minimal estrogen and condylar overloading act synergistically to accelerate condylar resorption. Conversely, OVX and ORX mice devoid of TMJ overload did not manifest condylar destruction (17,39). While the primary cause of ICR/PCR remains unclear, intrinsic factors including sex hormone deficiency and immune disturbance may contribute to its development and advancement of ICR/PCR in conjunction with extrinsic factors such as excessive and/or abnormal mechanical stress resulting from orthodontic treatment, orthognathic surgery, and occlusal disturbance.

In contrast, excessive released estrogen as seen in teenage girls immediate after menarche might also be an intrinsic factor of ICR/PCR onset. Ye et al. (30) investigated the impact of imbalanced occlusion and high-physiological estrogen on the TMJ condyle using experimental rats with unilateral anterior crossbite. They showed that high estrogen levels can damage condylar cartilage. However, it may have a protective effect on the subchondral bone in the early stages of TMJOA.

Orthognathic surgery is also associated with excessive and/or abnormal mechanical stress in the TMJ. Patients suffering from active condylar resorption and either concomitant or resultant maxillofacial skeletal discrepancies who are treated only with orthognathic surgery often encounter suboptimal outcomes and considerable relapse (40-42). This suggests that patients presenting with TMJ symptoms prior to surgery and requiring mandibular advancement are at a higher risk of PCR. Sakagami et al. (43) developed rat models with condylar resorption through mandibular distraction osteogenesis and indicated that rapid deformation of the condyle with cartilage destruction and bone resorption was caused by artificial distraction. Nogami et al. (31) and Katagiri et al. (32), using this rat model with condylar resorption, investigated the effects of conditioned medium from mesenchymal stem cells on condylar resorption. In these studies, severe condylar resorption occurred after mandibular distraction osteogenesis for 10 days.

Recently several researchers have developed the ICR animal model through surgically anterior disc displacement (33,34). As described above, anterior disc displacement might be induced by excessive or unbalanced stress in the TMJ, leading to TMJOA (26). Iwasaki et al. (34) developed a rabbit model that combined surgically induced anterior disc displacement with estrogen deficiency. This demonstrated the combined impact of disc displacement and estrogen deficiency on condylar resorption. This model helps us to understand how ICR starts. In addition, Shibusaka et al. (33) investigated the impact of anterior disc displacement and estrogen deficiency on the mandibular condyle. They demonstrated that estrogen deficiency amplifies the bone-resorptive and inflammatory effects of anterior disc displacement. It also accelerates condylar resorption and highlights the interplay between hormone imbalance and disc derangement in the TMJ degradation.

Discussion

Based on growing evidence associated with the etiology of TMD, numerous animal models of TMD have been established to aid the development of medications and devices for its treatment (Table 2). However, there is currently no gold-standard TMD animal model. Animal models developed to explore the mechanisms of TMD onset and progression include surgical procedures such as disc perforation (44), discectomy (45), and disc displacement (26), the intra-articular injection of chemicals such as adjuvant, iodoacetate, and collagen (46-48), gene knockouts such as MRL/lpr/lpr mice, biglycan/firomodulin double-deficient mice, and osteoblast-specific mutant TGF-β1 transgenic mice (49-52,97), chronic sleep deprivation (CSD) (53-58), obesity (59,60), spontaneous models (61-64), extra-articular stimulation by forced mouth opening (65-72), intraoral appliance (73-75,98), and experimental malocclusion including unilateral or bilateral anterior crossbite, spaced arch by separating elastics, and occlusal interference (76-96,99-102). The latter three models are referred to as the dental-stimulated TMD model.

CSD has been considered a well-validated method for inducing TMJ injury in animal models (55,58). Compared to other methods, CSD is highly effective and has few confounding factors (53), although it may only induce the initial stage of TMJOA, which is characterized by mild damage to the articular cartilage.

Obesity is a known possible risk factor for OA (103). High-fat diet (HFD) models in mice have shown TMJ cartilage degradation, elevated inflammatory markers (IL-1β, MMP-3), and increased leptin expression—an obesity-related proinflammatory factor (59) and altered miRNA in extracellular vesicles (60). While HFD-induced models of TMJOA have been established, further research is needed to uncover the underlying mechanisms linking obesity and TMJOA.

Spontaneous models such as STR/Ort and SAMP8 mice are likely to present TMJOA-like lesions with age, without external intervention (61-63). The disease progresses slowly and resembles primary TMJOA in humans. These models are useful for studying cartilage degradation and bone remodeling mechanisms. For example, STR/Ort mice show upregulation of inflammatory factors such as IL-6 and MMP-12 and may result in chronic inflammation and cartilage degradation of the TMJ in vivo (64), while SAMP8 mice exhibit downregulation of the Indian hedgehog signaling pathway and occlusal dysfunction accelerates progression toward degenerative TMJ disease in this model (65). Although studies using these models are limited and costly, they remain valuable tools for investigating the pathogenesis of TMJOA, especially when human tissue samples are difficult to obtain. Taking together, several developed animal models of TMJOA should be selected depending on the research objectives.

Recent advances in animal models of TMD have led to more accurate replication of human disease processes in combination with dental-stimulated TMD models. Mechanical loading models and chemical induction using agents such as monosodium iodoacetate (MIA) or complete Freund’s adjuvant (CFA) now closely mimic human TMD with TMJ pain (88). Genetically modified models, such as Adamts5 knockout mice, have revealed key molecular mechanisms of cartilage degradation (104). Imaging technologies such as micro-computed tomography (CT), magnetic resonance imaging (MRI), and optical coherence tomography enable non-invasive, longitudinal monitoring of TMJ structures (105). In addition, behavioral assays assessing spontaneous pain-related behaviors have refined pain measurement in TMD models (106). Recognition of sex differences has also become a research priority, with studies investigating hormonal influences on TMJ pathology (107). Advances in 3D bioprinting provide tissue-engineered TMJ scaffolds for investigating regenerative strategies (108), and combination models incorporating mechanical, inflammatory, and genetic factors now better reflect the multifactorial nature of human TMD (109).

Looking forward, the future of TMD animal research emphasizes more translationally relevant models that incorporate psychosocial stressors, given their critical role in human TMD pathogenesis (110). There is an urgent need for chronic, progressive TMD models to replicate the slow disease progression seen clinically (111). Humanized or personalized animal models using patient-derived stem cells offer potential for individualized therapy testing (112). Regenerative therapies, including mesenchymal stem cells and CRISPR gene editing, represent an exciting therapeutic frontier (113).

Regarding ICR/PCR animal models, the combination of estrogen deficiency and mechanical stress emerges as the most compelling and physiologically relevant approach for modeling ICR/PCR (28,29). Experimental rabbit and mice models that integrate OVX-induced estrogen loss with anterior disc displacement or occlusal overload consistently produce the most pronounced condylar degeneration—markedly reduced trabecular bone, cartilage thinning, enhanced osteoclastic activity and elevated degenerative scores—demonstrating a clear synergistic effect resulting in bone-resorptive changes (33,34). Owing to substantial heterogeneity across species (rabbits vs. rats/mice), surgical vs. overload protocols, endpoints (histology vs. imaging), and follow-up timing, standardized comparisons remain elusive in-spite of promising results. This variability highlights the urgent need to establish an accepted gold-standard ICR/PCR animal model, with harmonized parameters including animal choice, estrogen manipulation method, mechanical stress protocol, and outcome measures. Given the multifactorial etiology of human ICR/PCR—including intrinsic factors like sex‑hormone deficiency, immune disturbance, and extrinsic factors such as orthodontic load, orthognathic surgery, or occlusal imbalance—future model design must intentionally integrate multiple factors rather than relying on one variable alone. The strongest preclinical evidence supports combining estrogen deficiency with controlled mechanical overload in a standardized, reproducible protocol to better mirror human pathogenesis.

Conclusions

Judging from reviewing ICR/PCR animal models, it is obvious that the combination of estrogen deficiency and mechanical stress on mandibular condyles is the most promising approach, as demonstrated by studies showing that estrogen deficiency amplifies the bone-resorptive and inflammatory effects of anterior disc displacement. Furthermore, as ICR/PCR is considered a multifactorial disease involving both intrinsic and extrinsic factors, incorporating multiple factors rather than single-factor approaches is beneficial for developing ICR/PCR animal models. On the other hand, the causes and risk factors for condylar resorption remain unknown, and research on condylar resorption is still ongoing. In addition to the question of why condylar resorption occurs, there are many other questions that still need to be resolved, such as why the condylar resorption specifically happens in the TMJ and what the difference is between patients who develop condylar resorption and those who do not. In solving these questions, it is essential to develop precise animal models of condylar resorption. Due to the heterogeneity in study design, animal species, and modeling methods, a standardized comparison across studies is difficult. The development of a gold standard for animal models of ICR/PCR is eagerly awaited.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA-ScR reporting checklist. Available at https://fomm.amegroups.com/article/view/10.21037/fomm-25-12/rc

Peer Review File: Available at https://fomm.amegroups.com/article/view/10.21037/fomm-25-12/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://fomm.amegroups.com/article/view/10.21037/fomm-25-12/coif). E.T. serves as an unpaid editorial board member of Journal of Biomechanics from 2009 to present, Journal of Clinical Medicine from June 2022 to present, Frontiers of Oral Maxillofacial Medicine from May 2024 to December 2025 and Orthodontics and Craniofacial Research from 2007 to present, and an unpaid associate editor of Annals of Biomedical Engineering from 2009 to present and Frontiers in Bioengineering and Biotechnology from July 2022 to present. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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