Gene Mutations Associated with Temporomandibular Joint Disorders: A Systematic Review

Background The temporomandibular joint (TMJ) is a bilateral synovial joint between the mandible and the temporal bone of the skull. TMJ disorders (TMDs) are a set of complicated and poorly understood clinical conditions, in which TMDs are associated with a number of symptoms including pain and limited jaw movement. The increasing scientific evidence suggests that genetic factors play a significant role in the pathology of TMDs. However, the underlying mechanism of TMDs remains largely unknown. Objective The study aimed to determine the associated genes to TMDs in humans and animals. Methods The literature search was conducted through databases including Medline (Ovid), EMBASE (Ovid), and PubMed (NLM) by using scientific terms for TMDs and genetics in March 2015. Additional studies were identified by searching bibliographies of highly relevant articles and Scopus (Elsevier). Results Our systematic analyses identified 31 articles through literature searches. A total of 112 genes were identified to be significantly and specifically associated with TMDs. Conclusion Our systematic review provides a list of accurate genes associated with TMDs and suggests a genetic contribution to the pathology of TMDs.


Introduction
The temporomandibular joint (TMJ; aka the jaw joint) is a bilateral synovial joint between the mandible and the temporal bone. The TMJ consists of an articular disc located in the articular cavity, the glenoid fossa of the temporal bone and the mandibular condyle, and is filled with synovial fluid. The TMJ is unique because it consists of two joints in one bone, which is required to work simultaneously, and it acquires two major movements of the mandibular condyles: hinge and sliding, which is important for smoothly opening/closing mouth and chewing. TMJ disorders (TMDs) are a sub-classification of musculoskeletal disorders that result from stomatognathic system defects, and affect the function of masticatory muscles, the TMJ, and its associated structures [1].
TMDs are a set of complicated and poorly understood clinical conditions, which are associated with a number of symptoms including pain and limited jaw movement. The estimated prevalence of TMDs ranges from 5% to 60% worldwide [2]. TMDs occur as an individual disorder or associated with other syndromes, and TMJ pain is the second most common musculoskeletal pain after chronic low back pain [3] [4]. Since the symptoms of TMDs include pain, inflammation, and limited jaw movements, the etiology of TMDs may be complex. In addition, the susceptibility to TMDs may not be equal; for example, it is known that women are more susceptible than men. Severe and/or chronic cases of TMDs often occur with pain, but in mild cases, pain may be resolved over time. The possible influence factors of TMDs are mechanical and/or psychic stresses, hormones, genes, ethnicity, social status, and gender [5]. It has been postulated that women and adolescents have a higher risk for TMDs, compared to men [6] [7]. TMJ osteoarthritis (OA) is also diagnosed at the later stages of severe cases of TMDs [8]. The extent of causative genes of TMDs has been of prime interest [9]. The increasing scientific evidence suggests that genetic factors may play a significant role in the pathology of TMDs [10] [11]. However, the underlying mechanism of TMDs remains largely unknown. In this study, we performed a systematic review to identify genes associated with TMDs.
Currently, there are a few dental experts trained to precisely diagnose and treat this complex disorder. The treatment of TMDs has been very broad and general, including medications such as non-steroidal anti-inflammatory drugs (NSAIDs), muscle relaxants, physiotherapy, splints, biofeedback, and cognitive behavioral therapy. This study aims to provide precise information and highlight scientific literatures identifying genes associated with specific TMD conditions. Since not much research has been done on humans, animal studies have also been included in this systematic review. With knowledge of genetic studies, physicians and dentists can make diagnosis, tailor treatments, and predict susceptibility among people.

Eligibility Criteria for Systemic Review
The PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guideline and checklist was followed for this systematic review. Articles included in our systematic review met the following eligibility criteria: 1) described genes that are identified in TMDs; 2) were published as original articles (not as review articles, editorials, or comments); 3) were published in the English language; 4) were published between the years 2000 and 2015; and 5) specified TMD caused by gene mutations. Some articles were excluded from our systematic review because of one or more of the following reasons: a) gene mutations were not described in original articles; b) the type of TMDs (signs, symptoms, etc.) was not described or not diagnosed; c) the symptom was only pain, or the other symptoms and/or evaluations were not described; d) TMDs resulted from environmental factors; e) the studies had been done in other joints of the body; and f) others that include articles that failed to fit in any of the above criteria.

Information Sources and Search
The online databases that were searched included: Medline (Ovid), PubMed (National Library of Medicine), and EMBASE (Ovid). In addition, highly relevant citations were searched in Scopus (Elsevier) to determine if any unique studies were missed by the database searches. Bibliographies of highly relevant articles were also examined. The Primary Excel Workbook for Systematic Reviews was used to track all search strategies and results, as described previously [12]. All search strategies are listed in full in Table S1 and  Table S2. The search was limited to studies from 2000 through 2015 as genetic studies have become more technologically advanced in recent years, and very few genetic studies on TMDs were conducted before the year 2000.

Study Selection and Data Collection
RefWorks (Proquest) was used to store all citations found during the entire search process. The Primary Excel Workbook for Systematic Reviews (VonVille, Helena M. Primary Excel Workbook for Systematic Reviews, http://libguides.sph.uth.tmc.edu/excel_SR_workbook) was used to screen titles and abstracts of items found through database search. Titles and abstracts were screened by the first author (DS). The full text of articles not excluded was retrieved and reviewed by the first and second authors (DS, AS) with all data related to both screening and reviewing recorded in the Primary Excel Workbook. The data collected were displayed as a descriptive narrative. A codebook for data extraction from eligible articles was developed. The data elements that were extracted for the codebook included citation information, study level information (characteristics and results), and quality level information.

Results and Discussions
Nearly 900 unique articles were identified using the search strategies described above (see Figure 1 and Supplemental Information, Tables S1 and S2 for the database search strategies). Approximately 61% of the articles included were published after 2010. Interestingly, most of the articles included were published in 2014. Among the articles included for review (n = 31), 10 studies were done on humans while 21 studies were conducted on animal models (Table 1 and Table 2). One study conducted research on both mouse and human subjects [13]. 18 out of 31 articles conducted research on mice while 1 article studied in porcine, 2 articles in rats, and 1 article in rabbits. The articles from 2000-2015 covered most of the research related to genes in TMDs. Eight studies were conducted in 2014 and 2 studies were conducted in 2015. The demographic characteristics among the human studies were very different. Among the human studies, different ethnic groups such as Koreans, Japanese, Brazilian, Finnish, and Turkish populations were studied (Table 1). Three articles did not mention the ethnicity of the population studied [14] [15] [16]. One study indicated that in the miscegenetic Brazilian population, the age was significantly associated with TMDs [17]. Two studies were carried out only in women to determine the association of the estrogen receptor alpha (ESR1) gene with TMDs. One study [18] indicated the contribution of ESR1 on TMDs whereas another study [19] suggested no association of ESR1 with TMD symptoms such as clicks, crepitus, and bone erosion. Females are more affected by TMJ pain and degeneration due to the effects of β-estradiol on the TMJ [18]. Three studies show no statistically significant changes in candidate TMD causative genes: MAOA (monoamine oxidase-A), ESR1 (estrogen receptor alpha), and TNF (tumor necrosis factor alpha) [16] [19] [20]. Several polymorphisms have been described in the promoter region of MMP genes, and these polymorphisms modify gene expression and function of the MMPs. MMP1 (matrix metalloproteinase 1) polymorphism, but not MMP3 and MMP9 polymorphisms, is associated with osteophyte and erosion of the mandibular condyle. In the Brazilian MMP1 2G/2G homozygous subjects, the probability of developing degeneration of the mandibular condyle is 2.47 times higher than that in the MMP1 1G/2G and 1G/1G individuals [17]. ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motif 5) is involved in deformation of the articular disc associated with internal derangement and osteoarthritis in the TMJ [14]. Thus, proteinases contribute to degrade the articular disc and the surface of the mandibular condyle during the progression of TMDs. Homozygous polymorphism in ANKH (a human homolog of the murine progressive ankylosis gene, ank) more likely develops TMJ closed lock compared to controls [13]. The human leukocyte antigen (HLA) complex is a major histocompatibility complex (MHC) which is present on the surface of immune cells. Polymorphism in HLA-DRB1 (MHC class II, DR beta 1) allele is associated with erosion of the mandibular condyle [21]. These findings suggest that inflammation and autoimmune diseases may affect the progression of TMDs. Polymorphism in the fibroblast growth factor 2 (FGF2) gene is involved in the pathogenesis of TMJ synovial chondromatosis that is a rare proliferative disorder characterized by the formation of cartilaginous or osteocartilaginous nodules in synovium and articular cavities [15]. A recent genome-wide association study (GWAS) identified 22 independent loci showing association with degeneration of the mandibular condyle in East Asian populations. Among them, TSPAN9 (tetraspanin 9) polymorphism showed strongest association with TMD [22]. TSPAN9 mediates a signal transduction that plays a role in the regulation of cell development, activation, growth, and motility. Thus, some cell signaling pathways may be involved in the pathogenesis of TMDs. Although most of the studies have been done in small sample sizes, 28 out of 31 studies identified genes to be causal or associated with TMDs. This finding can lead us to believe that gene mutations are a causative factor for the incidence of TMDs.
In spite of extensive attempts, the molecular mechanism of TMDs is largely unknown because of the complex interaction of genes with other confounding factors like hormones, age, ethnicity, and environment. The presence of more than one symptom may be interdependent and act as a confounding factor [19]. Due to heterogeneity of symptoms, there are a lot of variations in diagnosis of TMDs worldwide. The appropriate treatments for TMD can only be initiated with a precise diagnosis. A number of imaging techniques including ultrasonography, computed tomography (CT), arthrography, and magnetic resonance imaging (MRI) have been adopted to confirm the diagnosis made by history taking and clinical examination. In 1992, The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) was proposed as the basis for diagnosis of these complicated disorders [23]. In 2004, RDS/TMD has been replaced with Diagnostic Criteria for TMD (DC/TMD) because the validity of RDC/TMD was not sufficient enough in clinic [24]. Only 2 studies used the RDC/TMD diagnostic criteria, and none of the clinical studies have used the latest DC/TMD criteria yet.
This systematic review has much strength in identifying causative genes and their genetic interactions; however, it has a few limitations such as the year range of 2000-2015 and the English language. All the human studies had more number of females participating in the study. The participation of unequal numbers of gender might affect the validity of the results that women are more susceptible to TMDs. In addition, due to a broad classification and diagnostic criteria of TMDs, a potent detection bias cannot be ignored. Publication bias also can be the reason for limited literature being published. Future research with larger sample sizes will enable us to better understand genetic association with TMDs. Recent advances have introduced new techniques like GWAS that can help us discover genes associated with TMDs.

Conclusion
From a public health perspective, there is an urgent need to address TMDs and determine their causative factors. Despite different diagnostic criteria used, most of the included studies find associations between genes and TMDs. Future studies should incorporate objective diagnostic methods such as DC/TMD for TMD diagnosis to yield consistent results. Understanding the molecular mechanism is important to individualize treatment for TMDs in order to alleviate the overall burden of TMDs. Further studies to identify genes associated with TMDs will enable us to specifically diagnose TMDs and improve the quality of treatment. These findings will also help us understand why there is a gender disparity in TMDs and who may be more likely to suffer from TMDs.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Acknowledgments
This study was supported by start-up fund to J.I.

ESR1
Estrogen Receptor Alpha  Prisma flowchart for selection of articles. Human studies.
Author publication year country of study Study population characteristics
Author publication year Animal studies TMD condition method of inducing Gene studied

Study limitations
Jing [25]  Igfbp3 Obvious OA-like changes were observed in 2 week female experimental group than those in control group (P < 0.01) and 2 week male experimental group (P < 0.05), Expression of IGF1 in the 2 week females was lower than males (P < 0.01), IGFR1 was significantly lower in 2 week female (P < 0.05) but increased in 2 week male experimental group, IGFBP3 in all female subgroups was significantly lower than that in their male counterparts