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.
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 [
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 [
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-inflam- matory 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.
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.
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 [
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.
Nearly 900 unique articles were identified using the search strategies described above (see
Author publication year country of study | Study population characteristics | Diagnosis diagnostic criteria | Gene(s) studied | Results | Study limitations |
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Planello [ | Mean Age of Cases 42.82 ± 14.96 N = 115: F = NR, M = NR Mean Age of Controls 38.04 ± 14.17 N = 117: F = NR, M = NR Ethnic status: Brazilian | Osteophytes, erosion, avascular necrosis, subchondral cyst, loose bodies, OA CT, Interview, MRI | MMP1 MMP3 MMP9 | Only MMP1 2G/2G genotype was found to be significant (P < 0.003). Effect of age on TMJ degeneration was significant (P < 0.002) | Small sample size to detect association of MMP3 gene |
Huang [ | Mean Age of Cases 15.5 to 69.7 N = 55: F = 44, M = 11 Mean Age of Controls NR N = NR: F = NR, M = NR Ethnic status: Japanese | TMJ clicking (disc displacement with reduction) or closed lock (disc displacement without reduction) and not having previous history of trauma, neoplasm and/or surgery in the TMJ; TMJ clicking used as controls Clinical evaluation, MRI | ANKH | Two alleles of ANKH-OR polymorphism were identified. ANKH-OR homozygotes were more likely to develop closed lock compared to controls (P = 0.011) | Calculation of minimal sample size was unattainable, Low response rate could have resulted in sampling bias, application of cohort study would have explored the influence of age on TMD, high percentage of patients were unwilling to take a blood test for assessment, study failed to indicate equivalence between fibrous ankylosis in mice and closed lock in humans |
Kim [ | Mean Age of Cases 31.45 ± 15.25 years N = 74: F = 50, M = 24 Mean Age of Controls 35.58 ± 12.47 N = 64: F = 41, M = 23 Ethnic Status: Korean | MPDS, IDD with reduction, IDD without reduction, OA, Osteoarthrosis RDC/TMD | ESR1 | No statistical difference between study group and control group (P > 0.5) | Small sample size |
Ribeiro-Dasilva [ | Age for Cases 18 - 44 N = 300: F = 300, M = 0 Age for Controls 31.1 ± 8.36 N = 100: F = 100, M = 0 Ethnic Status: White, Afro-American, Asiatic | Disc displacement with and without reduction, with limited mouth opening, without reduction and without limited mouth opening RDC/TMD | ESR1 | Presence of [GC] haplotype in ERα gene was higher in TMD with pain compared to control group (P = 0.0028) | Small sample size, admixed Brazilian population limits generalizability of data, only data from articular pain included and not muscular pain |
Matsumoto [ | Mean Age of Cases 50.11 N = 9: F = 8, M = 1 Mean Age of Controls 65.5 N = 2: F = 2, M = 0 Ethnic Status: NR | ID, OA NR | ADAMTS-5 | ADAMTS-5 is involved in deformation of the TMJ discs with ID and OA (P < 0.01) | Small sample size, limited use of TMJ disc cells |
Helenius [ | Mean Age of Cases 43.57 N = 84: F = 56, M = 28 Mean Age of Controls: NR N = 100: F = NR, M = NR Ethnic status: Finnish | RA, MCTD, AS, SPA ARA 1987 for RA, Alarcon-Segovia for MCTD, MNYC for AS, ESSG for SPA | HLA-DRB1 | In the whole patient population, HLA-DRB1 allele was significantly associated with TMJ erosions (P = 0.0014) | Controls were not clinically or radiologically examined |
Li [ | Mean Age of Cases NR N = 3: F = NR, M = NR Mean Age of Controls NR N = 3: F = NR, M = NR Ethnic status: NR | Synovial chondromatosis for cases; Open Reduction for controls NR | FGF2 | FGF2 was involved in the pathogenesis of synovial chondromatosis (P < 0.01) | NR |
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Yamaguchi [ | Mean Age of Cases Japanese 25.6 Koreans 28.5 N of Japanese = 105: F = 93, M = 12 N of Koreans = 41: F = 23, M = 18 Mean Age of Controls Japanese 25.6 Koreans 28.5 N of Japanese = 193 F = 141, M = 53 N of Koreans = 181 F = 70, M = 111) Ethnic status: East Asian | Osteophytes, erosion, flattening of TMJ bone Interview, CT, MRI, Panoramic Radiograph | APOL3 APP CCDC81 EXT2 FRMD4A FSTL4 LOC100506274 MRC2 N4BP1 OXR1 PCSK5 SLC24A4 THRB TPSAN9 ULK4 ZNF618 | All the genes were found to be significantly associated. TSPAN9 showed strongest association (P = 8.1 × 10−6) | Small sample size, age and gender differed between Japanese and Korean data sets |
Etoz [ | Mean Age of Cases 21.1 ± 12.1 N = 98; F = 75, M = 23 Mean Age of Controls 22.9 ± 10.1 N = 132: F = 104, M = 28 Ethnic Status: Turkish | Difficulty or pain while opening mouth, locking of jaw, pain, noises, unusual bite, frequent headache, MRI findings-NR Anamnestic Questionnaire clinical investigation, MRI | TNF | TNFα-308GApolymorphism is not associated with TMD | NR No radiological diagnosis |
Mutlu [ | Mean Age of Cases: 22.8 ± 3.6 years; N = 93; F = 73, M = 20 Mean Age of Controls 21.10 ± 3.7 N = 91: F = 61, M = 30 Ethnic Status: NR | Difficulty or pain while opening mouth, locking of jaw, pain, noises, unusual bite, frequent headache, MRI findings-NR Anamnestic Questionnaire clinical investigation, MRI | MAOA | No evidence to support the involvement of MAOA gene in TMD | NR No radiological diagnosis |
NR: Not Reported; RA: Rheumatoid Arthritis; MCTD: Mixed Connective Tissue disease; AS: Ankylosing Spondylitis; SPA: Spondyloarthropathy; ARA: American Rheumatism Association; MNYC: Modified New York Criteria; ESSG: European Spondyloarthropathy Study Group; ID: Internal Derangement; OA: Osteoarthritis; MPDS: Myofacial Pain Dysfunction Syndrome; MRI: Magnetic Resonance Imaging; CT: Computed Tomography.
age was significantly associated with TMDs [
Author publication year | Animal studies | TMD condition method of inducing TMD | Gene studied | Results | Study limitations |
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Jing [ | Mice | Mutant condylar cartilage Conditional Osxknockout (cKO) mice were generated by crossing Osx-loxP mice to Aggrecan-Cre mice. Cre activity induced by Tamoxifen injection | Osx | Defect in coupling chondrogenesis and osteogenesis in cKO mice, calcified cartilage in hypertrophic zone, few signs of endochondral bone formation, disorganized intramembranous bone | NR |
Ishizuka [ | Mice | OA-like changes Mechanical stress | Samp8 | Abnormal condylar organization, condylar degeneration, decreased chondroprogenitor cell proliferation and increased cell death | NR |
Li [ | Mice | Disc Disorder Knock-in mouse line with replacement of mouse Shox2 by the human SHOX coding sequence | Shox2 | Genetic association with congenital articular disc degeneration, suggesting that SHOX2 represents a susceptible locus for OA of the TMJ | NR |
Jiao [ | Mice | Cartilage degradation Green fluorescent protein mice were crossed with Cre mice | Tgfb1 | Abnormalities in the subchondral bone which induced cartilage degradation | Small sample size |
Inman [ | Mice | Syngnathia, agenesis of TMJ Crossbreeding | Foxc1 | Foxc1−/−mutant mice exhibit bilateral fusion of the upper jaw zygomatic complex to the dentary bone (syngnathia) | NR |
Ricks [ | Mice | OA Heterozygous mice (Dmm/+) of a C3H strain were crossed to produce wildtype(+/+) and Dmm/+ mice | Col2a1 | TMJ in Dmm/+ mice displayed premature articular cartilage and greater defects in chondrocyte arrangement, known biomarkers of OA were significantly expressed (P < 0.01) | NR |
Yasuda [ | Mice | Abnormal endochondral ossification and Class 3 dental malocclusion, shortening of cranial base Knock-in mutation in exon 7 of Fgfr3 gene | Fgfr3 | Articular disc fused with temporal bone, articular surface developed fissures, defects in endochondral ossification, abnormal glenoid fossa, defective trabecular bone formation | NR |
Purcell [ | Mice | NR Inactivation of genes Spry1, Spry2 | Spry1 Spry2 | Combined inactivation of Spry1 and Spry2 genes leads to absence of glenoid fossa and overgrowth of lateral pterygoid and temporalis muscles | NR |
Huang [ | Mice | Internal derangement Commercially bred ank/ank mutant mice were purchased | Ank | Fibrous ankylosis, narrower and/or ankylosed superior and inferior synovial cavities filled with fibrous connective tissue throughout the entire joint space | Utilization of 3-to-5 month old mice in this study might be responsible for the absence of erosive changes in the TMJ. |
Embree [ | Mice | OA Differential gene expression analysis was performed with RNA extracted from 3-week old WT and bgn−/+; fmod−/− | 4833416E15Rik Aebp1, Ahsp Angptl7, Arsk Bace1, Bgn Cartpt, Col2a1 Col9a1, Col9a3 Fmod, Hapln1 LOC 344564 Matn3, Mrpl30 Pfn1, Ptprv Rps19, Sfrp1 Slc4a1, Tspan33 | The microarray analysis discovered 22 genes differentially expressed in bgn−/+; fmod−/− mouse model that could be involved in disease initiation. 5 genes (Cartpt, Sfrp1, Arsk, Slc4a1, Ptprv) changed in the mouse models and are related to osteoclast f unction/differentiation and bone turnover | NR |
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Purcell [ | Mice | Targeted disruption of the Gli2 zinc finger domain (Gli2zfd/zfd) Crossbreeding | Gli2 | TMJ disk was missing, small condyle, cellular organization of growth plate was lost | NR |
Gu [ | Mice | Inactivation of Shox2 Shox2 conventional knock out mice and mice with floxed Shox2 allele were generated. Wnt1-Cre;Shox2F/F obtained by mating | Shox2 | Dysplasia of glenoid fossa, congenital TMJ ankylosis | NR |
Shibukawa [ | Mice | Absence of articular disc Absence of joint cavities Crossbreeding and induced mutation | Ihh | Mandible development was defective, condyle zonal architecture was abnormal, complete absence of functional disc and joint cavity | NR |
Meng [ | Mice | OA Surgical lesion on discs, gene expression profile | Angpt12, Aqp3 Baalc, Casr, Cav, Chad, Cldn11, Cls Clu, Crabp2 Csrp2, Dkk3 Dpt, Egln3 Eln, Gda, Gda, Hig1 Hspca, Htr2a Igfbp5, Igfbp6 Il11ra1, Lg11 Lg11, Lib Meox2, Mmp3 Nb11, Nov Nr1d1, Nt5 Octnl, Plat Prelp, Prrx2 Pthlh, Scrg1 Serpina1, Sfrp4 Sod3, Spin2c Spp2, Tgfbi Thbs4, Tnfrsf11b Tnmd | Swelling, superficial fibrillation, early osteoarthritic changes | NR |
Xu [ | Mice | Cartilage Degeneration Heterozygous cho/+ mutant mice | cho | At age 6 months OA-like changes became more severe, including flattening of the condylar head, loss of proteoglycans, and a reduced hypertrophic zone | NR |
Gu [ | Mice | Apoptotic cells Wnt1-Cre; Bmpr1aF/F embryos obtained by crossing Wnt1-Cre; Bmpr1aF/+ with Bmpr1aF/F line | Bmpr1a | Agenesis Failed formation of functional fibrocartilage layer, Failure of disc separation from hypoplastic condyle | NR |
Li [ | Mice | Dysplasia Cross of Wnt-Cre mice with pMes-stopShox2 mice | Shox2 | Increased number of apoptotic cells in the glenoid fossa causing glenoid fossa dysplasia, dysplasia of condyle | NR |
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Wang [ | Mice | TMJ Cartilage Degeneration Crossbreeding to generate β-catenin(ex3)Col2ER, Tamoxifen administered | Ctnnb1 | Significant reduction in TMJ joint space, cartilage thickness was significantly decreased, increase in cartilage degrading enzymes, OA-like phenotype | NR |
Meng [ | Rats | OA Surgically, lesions created in discs | Aqp1 Aqp3 | High expression and different localization of AQP3 in OA cartilage. No significant difference between OA and normal controls | NR |
Yu [ | Rats | Condyle cartilage Degeneration Occlusal treatment carried out to induce degenerative changes in the mandibular condylar cartilage | Igf1 Gfr1 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 | Differences in occlusion between rats and humans |
Asakawa-Tanne [ | Porcine | Disc indentation Porcine cranial heads were subjected to cyclic loading | Cox2 Il1b Mmp1 Mmp3 Mmp9 | Compromised lubrication in TMJ is associated with altered frictional properties and surface wear of condylar cartilage | Amount and nature of loading used in the study do not represent the actual TMJ dynamics in vivo |
Ge [ | Rabbit | Cartilage destruction Primary rabbit condylar chondrocytes were treated with IL-β, purified WNT5A protein, or both and transfected with Wnt5a expression vector | Wnt5a | WNT5A is associated with cartilage destruction by promoting expression of MMP1, MMP3, MMP9, MMP13 | NR |
NR: Not reported; OA: Osteoarthritis.
likely develops TMJ closed lock compared to controls [
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 [
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.
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.
This study was supported by start-up fund to J.I.
The authors declare that they have no competing interests.
D. Sangani and H. VonVille performed literature search and drafted the article. A. Suzuki revised the manuscript for intellectual content. J. Hixson was involved in the discussion of the conception and results of the study. J. Iwata made substantial contributions to the conception and design of the paper, drafted and revised the article critically for important intellectual content and involved in the final approval of the version to be published. All authors read and approved the final manuscript.
Dhruvee Sangani,Akiko Suzuki,Helena VonVille,James E. Hixson,Junichi Iwata, (2015) Gene Mutations Associated with Temporomandibular Joint Disorders: A Systematic Review. Open Access Library Journal,02,1-14. doi: 10.4236/oalib.1101583
DC/TMD: Diagnostic Criteria for TMD
ESR1: Estrogen Receptor Alpha
GWAS: Genome-Wide Association Study
MAOA: Monoamine Oxidase-A
NSAIDs: Non-Steroidal Anti-Inflammatory Drugs
PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses
RDC/TMD: Research Diagnostic Criteria for Temporomandibular Disorders
TMDs: Temporomandibular Joint Disorders
TMJ: Temporomandibular Joint
TNF: Tumor Necrosis Factor Alpha
Table | Vendor/ Interface | Database | Date searched | Database update | Searcher(s) |
---|---|---|---|---|---|
1a | Ovid | Medline® | 2/25/2015 | 1996 to February Week 3 2015; In-Process & Other Non-Indexed Citations February 24, 2015 | Helena M. VonVille; Dhruvee Sangani |
1b | National Library of Medicine | PubMed | 1/28/2015 | 1/28/2015 | Helena M. VonVille; Dhruvee Sangani |
1c | Ovid | Embase® | 1/29/2015 | 1974 to 2015 January 27 | Helena M. VonVille |
ID | Variable name (coding instructions) | Values, text codes | |
---|---|---|---|
Citation information | |||
C 1 | Ref ID | (Numerical) (ranges from 1-1010) | |
C 2 | Name of coder | ||
C 3 | Publication date | YYYY (ranges from 2000-2015) | |
C 4 | Author | ||
C 5 | Type of citation | Full text (from journal article) | |
C 7 | Secondary cite(s)- Ref ID #, publication date, author, journal | ||
C8 | Number of studies reported in this citation | Note: default = 1 | |
Study level information (characteristics and results) | |||
Study design | Laboratory experiment/translational research | ||
Other (specify): | |||
S 3 | Study location-state/province, city, & country: | ||
S 4 | Sponsor (check one) | Industry sponsored | |
Cannot be ascertained | |||
Other (specify) | |||
S 5 | Type of TMD disorder alphabetize list | Agenesis | |
Ankylosis | |||
Disc derangement | |||
Dysplasia | |||
Internal derangement | |||
Osteoarthritis | |||
Syngnathia | |||
Other (specify) | |||
S 6 | Species | Humans | |
Animals a) Mice; b) Rabbit; c) Rat; d) Sheep Other (Specify) | |||
S 7 | Gene(s) studied | List out all genes | |
Quality level information |
Q 1 | Did the study describe the method of embryo collection and genotyping? | 1-Yes 2-No 3-NA |
---|---|---|
Q 2 | Did the study describe eligibility criteria and methods used to select participants? | 1-Yes 2-No 3-NA |
Q 3 | Were the statistical analysis reported? | 1-Yes 2-No 3-NA |
Q 4 | Did the study describe the trial design? | 1-Yes 2-No 3-NA |
Q 5 | Did the study explain sample size calculations | 1-Yes 2-No 3-NA |
Q 7 | Did the study describe blinding? | 1-Yes 2-No 3-NA |
Q 8 | What were the key limitations according to the authors? | |
Q9 | Did the authors discuss the external validity? | 1-Yes 2-No 3-NA |
Q 10 | Did the study describe eligibility criteria and methods used to select participants? | 1-Yes 2-No 3-NA |
Q 12 | Was the association of genes with TMJ Disorders clearly described? | 1-Yes 2-No 3-NA |
Q 13 | Was the study outcome defined? | 1-Yes 2-No 3-NA |
Q 14 | Did the study describe any measures to minimize potential sources of bias? | 1-Yes 2-No 3-NA |
Q15 | Did the study explain how was sample size arrived at? | 1-Yes 2-No 3-NA |
Q 18 | What were the key limitations according to the authors? |