Causal relationship between hypothyroidism and temporomandibular disorders: evidence from complementary genetic methods.

BACKGROUND: The role of thyroid health in temporomandibular disorders (TMDs) has been emphasized in observational studies. However, whether the causation exists is unclear, and controversy remains about which specific disorder, such as hypothyroidism or hyperthyroidism, is destructive in TMDs. This study aims to investigate the overall and specific causal effects of various thyroid conditions on TMDs. METHODS: Mendelian randomization (MR) studies were performed using genetic instruments for thyrotropin (TSH, N = 119,715), free thyroxine (fT4, N = 49,269), hypothyroidism (N = 410,141), hyperthyroidism (N = 460,499), and TMDs (N = 211,023). We assessed the overall effect of each thyroid factor via inverse-variance weighted (IVW), weighted median, and MR-Egger methods, and performed extensive sensitivity analyses. Additionally, multivariable MR was conducted to evaluate the direct or indirect effects of hypothyroidism on TMDs whilst accounting for TSH, fT4 and hyperthyroidism, and vice versa. RESULTS: Univariable MR analyses revealed a causal effect of hypothyroidism on an increased risk of TMDs (IVW OR: 1.12, 95% CI: 1.05-1.20, p = 0.001). No significant association between genetically predicted hyperthyroidism, TSH, or fT4 and TMDs. In the multivariable MR analyses, the effects of hypothyroidism on TMDs occurrence remained significant even after adjSusting for TSH, fT4 and hyperthyroidism (multivariable IVW OR: 1.10, 95% CI: 1.03-1.17, p = 0.006). No pleiotropy and heterogeneity were detected in the analyses (p > 0.05). CONCLUSIONS: Hypothyroidism might causally increase the risk of TMDs through a direct pathway, highlighting the critical role of managing thyroid health in the prevention of TMDs. Clinicians should give heightened attention to patients with hypothyroidism when seeking medical advice for temporomandibular discomfort. However, caution is warranted due to the potential confounders, pleiotropy, and selection bias in the MR study.

Causal effects of educational attainment on temporomandibular disorders and the mediating pathways: A Mendelian randomization study.

BACKGROUND: As one of the most important indicators of socioeconomic status, educational attainment (EA) exhibits a strong association with temporomandibular disorders (TMDs). Despite this link, there is a lack of evidence regarding the causal role of EA in either facilitating or preventing TMDs. OBJECTIVE: This study aimed to investigate the causal effect of education on TMDs and explore potential mediating pathways. METHODS: Utilizing summary statistics from genome-wide association studies on years of schooling (N = 766 345) and TMDs (N = 211 023), we conducted Mendelian randomization (MR) to assess the overall effect of education. Additionally, a two-step MR approach was employed to evaluate 30 potential mediators and calculate the mediation proportions in the association. Comprehensive sensitivity analyses were used to verify the robustness, heterogeneity, and pleiotropy. RESULTS: Univariable MR analyses revealed a causal effect of lower EA on an increased risk of TMDs (OR: 0.53, 95% CI: 0.43-0.66, p < .001). Five out of 30 modifiable factors were identified as causal mediators in the associations of EA with TMDs, including feeling nervous (mediation proportion: 11.6%), feeling tense (10.2%), depression (9.6%), feeling worry (7.6%) and daily smoking (8.9%). Meanwhile, no pleiotropy was detected in the analyses (p > .05). CONCLUSION: Our findings supported that higher EA has a protective effect on the onset of TMDs, with partial mediation by psychological disorders and daily smoking. Interventions on these factors thus have the potential of substantially reducing the burden of TMDs attributed to low education.

The association of gene polymorphisms in catechol-O'methyltransferase (COMT) and ß2-adrenergic receptor (ADRB2) with temporomandibular joint disorders.

OBJECTIVE: Temporomandibular disorder (TMD) has a multifactorial etiology that includes environmental, psychological, and genetic factors. This study aimed to evaluate the possible relationship between polymorphisms in Catechol-O-methyltransferase (COMT) and ß2-adrenergic receptor (ADRB2) genes with TMD. DESIGN: This observational case-control study included 80 patients and 70 healthy controls. The diagnosis of TMD was made using the diagnostic criteria for TMD and the following TMD categories were used for the case group: muscular TMD and articular TMD (disc displacement and arthralgia). A genotyping study of gene polymorphisms in COMT (rs 9332377) and ADRB2 (rs20530449) was performed from genomic DNA isolated from blood. The chi-square test was used to analyze the relationships. P < 0.05 was accepted as a significant difference. RESULTS: The polymorphic TT and CT genotype for COMT (rs rs9332377) was significantly higher in the articular TMD group while the non-polymorphic CC genotype was significantly lower in the articular TMD group (P < 0.05). Regarding ADRB2 (rs20530449), the polymorphic GG genotype was similarly considerably more common in the articular TMD group (p < 0.05). In addition, the T allele in the COMT (rs rs9332377) gene was found to be significantly higher in the articular TMD group (p < 0.05). CONCLUSIONS: In the Turkish population, gene polymorphisms in COMT (rs9332377) and ADRB2 (rs2053044) were associated with articular TMD. This study supports the hypothesis that changes in COMT and ADRB2 genes may play a role in temporomandibular joint pain and predisposition to TMD.

Causal relationship between psychiatric traits and temporomandibular disorders: a bidirectional two-sample Mendelian randomization study.

OBJECTIVES: This study was to investigate the causal relationship between temporomandibular disorders (TMD) and psychiatric disorders by Mendelian randomization (MR) analysis. MATERIALS AND METHODS: A two-sample bidirectional MR analysis was adopted to systematically explore the causal relationship between TMD and eight psychiatric traits, including anxiety disorder (AD), panic disorder (PD), major depressive disorder (MDD), neuroticism, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BIP), and schizophrenia (SCZ). Inverse variance weighted (IVW), weighted median, and MR-Egger regression were used in my study. Furthermore, we also performed three sensitivity analyses to illustrate the reliability of the analysis. RESULTS: Two psychiatric traits have risk effects on TMD: PD (OR = 1.118, 95% CI: 1.047-1.194, P = 8.161 × 10-4, MDD (OR = 1.961, 95% CI: 1.450-2.653, P = 1.230 × 10-5). Despite not surpassing the strict Bonferroni correction applied (P > 0.00625), we could think that there was a suggestive causal effect of neuroticism and SCZ increasing the risk of TMD. On the reverse MR analysis, we found no significant evidence of causal effects of TMD on these psychiatric traits. Except for heterogeneity in the causal analysis for SCZ on TMD, no heterogeneity and horizontal pleiotropy were detected in the other analyses. CONCLUSIONS: Our two-sample MR study has provided further evidence of PD and MDD being related to a higher risk of TMD. CLINICAL RELEVANCE: These findings highlight the importance of closely monitoring mental traits during future TMD treatments to prevent an increased risk of TMD.

Loss of miR-204 and miR-211 shifts osteochondral balance and causes temporomandibular joint osteoarthritis.

Temporomandibular joint (TMJ) osteoarthritis (OA) is a common type of TMJ disorders causing pain and dysfunction in the jaw and surrounding tissues. The causes for TMJ OA are unknown and the underlying mechanism remains to be identified. In this study, we generated genetically-modified mice deficient of two homologous microRNAs, miR-204 and miR-211, both of which were confirmed by in situ hybridization to be expressed in multiple TMJ tissues, including condylar cartilage, articular eminence, and TMJ disc. Importantly, the loss-of-function of miR-204 and miR-211 caused an age-dependent progressive OA-like phenotype, including cartilage degradation and abnormal subchondral bone remodeling. Mechanistically, the TMJ joint deficient of the two microRNAs demonstrated a significant accumulation of RUNX2, a protein directly targeted by miR-204/-211, and upregulations of ß-catenin, suggesting a disrupted balance between osteogenesis and chondrogenesis in the TMJ, which may underlie TMJ OA. Moreover, the TMJ with miR-204/-211 loss-of-function displayed an aberrant alteration in both collagen component and cartilage-degrading enzymes and exhibited exacerbated orofacial allodynia, corroborating the degenerative and painful nature of TMJ OA. Together, our results establish a key role of miR-204/-211 in maintaining the osteochondral homeostasis of the TMJ and counteracting OA pathogenesis through repressing the pro-osteogenic factors including RUNX2 and ß-catenin.

Association between periodontitis and temporomandibular joint disorders.

BACKGROUND: Periodontitis (PD) may affect temporomandibular joint disorders (TMD) and TMD may influence PD in previous observational studies. Nevertheless, these studies were prone to confounders and reverse causation, leading to incorrect conclusions about causality and direction of association. This research investigates the associations between PD and TMD employing bidirectional two-sample Mendelian randomization (MR) analysis. METHODS: Single-nucleotide polymorphisms (SNPs) related to PD (p < 5 × 10-6) were selected from a genome-wide association study (GWAS) from the Gene-Lifestyle Interaction in the Dental Endpoints (GLIDE) consortium, and related these to SNPs from FinnGen and UK Biobank (UKB) consortia, and vice versa. We implemented the standard inverse variance weighted (IVW), weighted median (WM), MR-Egger regression, and MR-PRESSO methods to estimate the potential causality between PD and TMD. Sensitive tests were conducted using robust MR methods. Results from FinnGen and UKB were combined using the fixed model. RESULTS: PD did not appear to causally affect TMD. Additionally, the reverse MR analysis did not reveal a significant causal effect of TMD on PD. The results of other MR methods were similar to those of the IVW method. Sensitivity analyses addressed no potential pleiotropy in MR estimations. Results from the meta-analysis were consistent with the above-mentioned consequences. CONCLUSION: This research does not support a causal relationship between PD and TMD. PD does not appear to worsen TMD directly, and vice versa.

Causal association between body mass index and temporomandibular disorders: a bidirectional two-sample Mendelian randomization analysis.

BACKGROUND: Observational studies have shown that body mass index (BMI) is highly correlated with the occurrence of temporomandibular disorders (TMDs). However, these studies failed to present a causal relationship. Thus, we aimed to performed a Mendelian randomization (MR) study to investigate causality between BMI and TMDs. METHODS: We performed a two-sample bidirectional MR analysis using large-scale genome-wide association studies (GWAS). Data were obtained from a large-scale BMI dataset (N = 322,154), TMDs dataset (N = 134,280). The causal effects were estimated with inverse-variance weighted (IVW) method, MR Egger, weighted median. Sensitivity analyses were implemented with Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis and the funnel plot. RESULTS: In the forward MR analysis, a genetic prediction of low BMI was causally associated with a higher risk of TMDs (IVW OR: 0.575, 95% CI: 0.415-0.798, p: 0.001). Similar results were obtained using other complementary methods (MR Egger OR: 0.270, 95% CI: 0.104-0.698, p: 0.009; weighted median OR: 0.496, 95% CI: 0.298-0.826, p: 0.007). In the reverse MR results, TMDs was shown to have no significant effect on BMI (all p > 0.05). No pleiotropy and heterogeneity were detected in the bidirectional analysis (p > 0.05). CONCLUSION: A lower BMI might be causally associated with increased risk of TMDs, supporting the importance of weight control for the prevention of TMDs. Clinicians should pay more attention to the low-BMI patients among those seeking medical advice due to temporomandibular joint discomfort.

Silencing of TRPV4-expressing sensory neurons attenuates temporomandibular disorders pain.

Identification of potential therapeutic targets is needed for temporomandibular disorders (TMD) pain, the most common form of orofacial pain, because current treatments lack efficacy. Considering TMD pain is critically mediated by the trigeminal ganglion (TG) sensory neurons, functional blockade of nociceptive neurons in the TG may provide an effective approach for mitigating pain associated with TMD. We have previously shown that TRPV4, a polymodally-activated ion channel, is expressed in TG nociceptive neurons. Yet, it remains unexplored whether functional silencing of TRPV4-expressing TG neurons attenuates TMD pain. In this study, we demonstrated that co-application of a positively charged, membrane-impermeable lidocaine derivative QX-314 with the TRPV4 selective agonist GSK101 suppressed the excitability of TG neurons. Moreover, co-administration of QX-314 and GSK101 into the TG significantly attenuated pain in mouse models of temporomandibular joint (TMJ) inflammation and masseter muscle injury. Collectively, these results suggest TRPV4-expressing TG neurons represent a potential target for TMD pain.

Painful Temporomandibular Joint Clicking: Genetic Point of View.

AIMS: To determine whether there is an association between gene polymorphisms and patients with painful temporomandibular joint (TMJ) clicking when compared to patients with painless TMJ clicking and a healthy control group. METHODS: In this pilot study, the genotypic and allelic frequencies of candidate single-nucleotide polymorphisms (SNP) were compared among 60 individuals divided equally into three groups: patients with painful TMJ clicking (n = 20); patients with painless TMJ clicking (n = 20); and healthy controls (n = 20). Participants were genotyped for the following SNPs using real-time polymerase chain reaction: MMP1 -16071G/2G, COMT Val158Met, TNFα -308, IL1ß +3954, IL6 -174, and IL10 -1082. The pressure pain threshold (PPT) of the TMJ was also assessed. All variables were compared among groups. RESULTS: Patients with painful TMJ clicking had a significant association and a higher frequency of MMP1 -16071G/2G (P = .042), COMT Val158Met (P = .030), and TNFα -308 (P = .016) when compared to the other groups, as well as a lower frequency of IL10 -1082. Considering PPT values, a progressively lower mean was found in individuals with painful TMJ clicking, followed sequentially by the painless TMJ clicking and the control groups. CONCLUSION: This pilot study showed that patients with painful TMJ clicking had a significant association with mutant genotypes related to degradation of extracellular matrix components, pain, proinflammation, and anti-inflammation. Furthermore, these patients also had significantly lower TMJ PPT values in all comparisons.

Temporomandibular disorder in construction workers associated with ANKK1 and DRD2 genes.

The study aimed to explore the influence of genetic polymorphisms in ANKK1 and DRD2 on the signs and symptoms of temporomandibular disorder (TMD) in construction workers. This cross-sectional study included only male subjects. All construction workers were healthy and over 18 years age. Illiterate workers and functionally illiterate workers were excluded. The diagnosis of TMD was established according to the Research Diagnostic Criteria for TMD (RDC/TMD). Genomic DNA was used to evaluate the genetic polymorphisms ANKK1 (rs1800497) and DRD2 (rs6275; rs6276) using Real-Time PCR. Chi-square or Fisher exact tests were used to evaluate genotypes and allele distribution among the studied phenotypes. The established alpha of this study was 5%. The sample included a total of 115 patients. The age of the patients ranged from 19 to 70 years (mean age 38.2; standard deviation 11.7). Chronic pain (87.7%), disc displacement (38.2%), and joint inflammation (26.9%) were the most frequently observed signs and symptoms. The genetic polymorphism rs6276 in DRD2 was associated with chronic pain (p=0.033). In conclusion, our study suggests that genetic polymorphisms in DRD2 and ANKK1 may influence TMD signs and symptoms in a group of male construction workers.

Calcitonin gene-related peptide: An intra-articular therapeutic target for TMJ disorders.

OBJECTIVES: The goal of this project was to evaluate the role of calcitonin gene-related peptide (CGRP) in the development of arthritis. METHODS: Herein, we employed somatic mosaic analysis in two different joints by FIV(CGRP) intra-articular inoculation in the knees or temporomandibular joints (TMJ) of young adult male C57/BL6 mice. FIV(CGRP) is a feline immunodeficiency virus over-expressing full-length CGRP. Joint pathology and function were evaluated at the histopathological and behavioral levels. In addition, CGRP signaling was inhibited by intra-articular inoculation using FIV(CGRP8-37 ), such that the inhibitory peptide CGRP(8-37) was overexpressed 4 weeks after induction of joint inflammation in the TMJ of IL-1ßXAT transgenic mouse model. The mice were evaluated for behavior and killed for evaluation of knee and TMJ pathology. RESULTS: Overexpression of CGRP in the joints of wild-type mice induced the development of joint anomalies, including meniscal hypertrophy and articular pathology, associated with nocifensive behavior. Intriguingly, overexpression of the CGRP(8-37) inhibitory peptide in the knee and TMJ of IL-1ßXAT transgenic mice with joint inflammation resulted in partial amelioration of the attendant joint pathology. CONCLUSIONS: The results of this study suggest that CGRP is sufficient and necessary for the development of joint pathology and may serve as an intra-articular therapeutic target using gene therapy or monoclonal antibody-based therapies.

[Mechanism of microRNA-100-5p on mammalian target of rapamycin in temporomandibular arthritis].

PURPOSE: To investigate the mechanism of microRNA-100-5p (miR-100-5p) on mammalian target (mTOR) of rapamycin in temporomandibular arthritis. METHODS: Sixty SD rats were randomly divided into group A, group B, group C, group D, and group E, with 12 rats in each group. Rat models of temporomandibular arthritis were prepared by injecting sodium iodoacetate solution into the bilateral spaces of temporomandibular joint. After establishment, group C was injected pcDNA3.1-miR-100-5p recombinant plasmid, group D was injected mTOR inhibitor rapamycin, group E was injected with pcDNA3.1-miR-100-5p recombinant plasmid and rapamycin, and group A was injected same amount of normal saline in the same way. Various indexes were observed in each group, including morphological changes of temporomandibular joint tissues, matrix metalloproteinase-3 (MMP-3), MMP-1, MMP-13, interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), miR-100-5p, mTOR expression. The data were processed using SPSS 22.0 software package. RESULTS: In group B, the structure of temporomandibular joint was fuzzy, with synovial hyperplasia, vascular dilatation, clustered cells and a large amount of inflammatory infiltration. Histopathological changes of temporomandibular joint in each interventional group were improved to different degrees compared with group B, among which group E showed the most obvious improvement. The levels of MMP-3, MMP-1, MMP-13, IL-6, IL-1ß and TNF-α in group B were significantly higher than those in group A(P＜0.05). The levels of MMP-3, MMP-1, MMP-13, IL-6, IL-1ß and TNF-α in group C, group D and group E were significantly lower than those in group B(P＜0.05). The levels of MMP-3, MMP-1, MMP-13, IL-6, IL-1ß and TNF-α in group D were not significantly different from those in group C (P＜0.05). The levels of MMP-3, MMP-1, MMP-13, IL-6, IL-1ß and TNF-α in group E were significantly lower than those in group D (P＜0.05). The expression level of miR-100-5p in group E was significantly higher than that in group B (P＜0.05). The expression level of mTOR protein in group E was significantly lower than that in group B (P＜0.05). CONCLUSIONS: MicroRNA-100-5p may alleviate temporomandibular arthritis by down-regulating the expression of mTOR.

TNF-α levels and presence of SNP-308G/A of TNF-α gene in temporomandibular disorder patients.

INTRODUCTION: Temporomandibular disorder (TMD) refers to a group of conditions that compromise the harmonious movement and function of the temporomandibular joint, masticatory muscles, and associated structures. The etiopathogenesis of TMD is multifactorial but not well-understood, with the role of genetic factors still being unclear. OBJECTIVE: This review aims to summarize the results of studies that evaluated TNF-α levels and the -308G/A TNF-α polymorphism in TMD patients. This study emphasizes the importance of a more selective treatment involving TNF-α inhibitors that can potentially reduce inflammation and pain, and improve quality of life. METHODS: The MEDLINE/PubMed database, Cochrane Library, and Web of Science database were searched for case-control studies published until September 2020 that compared levels of TNF-α or presence of its -308G/A polymorphism in TMD patients and healthy individuals. RESULTS: Six case-control studies were identified with a total of 398 TMD patients, aged between 12 and 78 years. The control group consisted of 149 subjects, aged between 18 and 47 years. The occurrence of TMD was predominant in females. Majority of studies found high TNF-α levels in TMD patients, compared to the control group. One of these studies found a positive correlation between the GA genotype and the development of TMD. CONCLUSION: Majority of the TMD patients showed elevated TNF-α levels, and a possible explanation for this could be the presence of the -308G/A polymorphism.

Mutations in the osteoprotegerin-encoding gene are associated with temporomandibular joint ankylosis.

OBJECTIVE: This study aimed to investigate genetic variations in the osteoprotegerin-encoding gene (TNFRSF11B) in patients with temporomandibular joint ankylosis (TMJA). STUDY DESIGN: The sample comprised 17 patients diagnosed with TMJA, of both sexes with ages ranging from 6 to 57 years old. TNFRSF11B mutational analysis was performed using the Sanger sequencing method with DNA extracted from oral cells, and the functional impact prediction of the variants was assessed using bioinformatic analysis. RESULTS: Sequencing analysis identified 15 (88.23%) patients that presented at least 1 genetic variant in TNFRSF11B. The mutation rs202090603 (p.E33K) was found in 6 individuals, and rs140782326 (p.V281M), rs11573942 (p.L295), and rs1375250340 (p.I389T) were identified in 1 subject each. According to the pathogenicity potential of mutations, 3 variants were considered of low impact (rs2073618, rs202090603, and rs2228568) and 3 as disease causing (rs140782326, rs11573942, and rs1375250340). The variant rs202090603 (p.E33K) was found in the first cysteine domain with differences in the loop positions of p.E33K mutated the 3D structure of osteoprotegerin. CONCLUSION: Two polymorphisms (rs2073618 and rs2228568) and the mutations rs202090603 (p.E33K), rs140782326 (p.V281M), rs11573942 (p.L295), and rs1375250340 (p.I389T) in the TNFRSF11B gene may be associated with TMJA.

Involvement of an FTO gene polymorphism in the temporomandibular joint osteoarthritis.

OBJECTIVES: The FTO gene has been reported as an obesity-associated gene and is also considered a risk gene for osteoarthritis (OA). However, its exact function is unclear, and there is conflicting evidence on the involvement of FTO polymorphisms in OA via obesity. The purpose of this study was to determine the effects of FTO polymorphism rs8044769 alleles on OA in the temporomandibular joint (TMJ), which is minimally affected by body weight. MATERIALS AND METHODS: A total of 324 TMJs (113 with OA and 211 without OA, serving as controls) from 162 Japanese patients with temporomandibular disorders and undergoing MRI examination were analyzed. Genotyping was conducted, and multivariate analysis was performed after adjusting for the effects of age, sex, body mass index, and TMJ disc abnormalities. RESULTS: Mean age, BMI, and sex did not differ between the TMJs with OA and the TMJs without OA, but a significant difference was found for positional and dynamic disc abnormalities (P < 0.05). The allele frequency of FTO polymorphisms also differed significantly between the TMJs with OA and the TMJs without OA (P = 0.011). Moreover, logistic regression analysis showed no significant association between BMI (P = 0.581) and the occurrence of TMJOA but also indicated that the CC allele of rs8044769 is a risk factor for TMJOA (P = 0.040). CONCLUSIONS: Our results show that rs8044769 in the FTO gene might be involved in TMJOA. CLINICAL RELEVANCE: The present study provides a basis for a deeper understanding of the mechanism underlying degenerative skeletal diseases and the more effective selection and development of treatment strategies based on the patients' genetic characteristics.

TNF-α levels and presence of SNP-308G/A of TNF-α gene in temporomandibular disorder patients

ABSTRACT Introduction: Temporomandibular disorder (TMD) refers to a group of conditions that compromise the harmonious movement and function of the temporomandibular joint, masticatory muscles, and associated structures. The etiopathogenesis of TMD is multifactorial but not well-understood, with the role of genetic factors still being unclear. Objective: This review aims to summarize the results of studies that evaluated TNF-α levels and the -308G/A TNF-α polymorphism in TMD patients. This study emphasizes the importance of a more selective treatment involving TNF-α inhibitors that can potentially reduce inflammation and pain, and improve quality of life. Methods: The MEDLINE/PubMed database, Cochrane Library, and Web of Science database were searched for case-control studies published until September 2020 that compared levels of TNF-α or presence of its -308G/A polymorphism in TMD patients and healthy individuals. Results: Six case-control studies were identified with a total of 398 TMD patients, aged between 12 and 78 years. The control group consisted of 149 subjects, aged between 18 and 47 years. The occurrence of TMD was predominant in females. Majority of studies found high TNF-α levels in TMD patients, compared to the control group. One of these studies found a positive correlation between the GA genotype and the development of TMD. Conclusion: Majority of the TMD patients showed elevated TNF-α levels, and a possible explanation for this could be the presence of the -308G/A polymorphism.

RESUMO Introdução: A disfunção temporomandibular (DTM) é definida como um grupo de alterações que comprometem a articulação temporomandibular, os músculos mastigatórios e as estruturas associadas. A etiopatogenia da DTM é multifatorial, e o papel dos fatores genéticos permanece obscuro. Objetivo: A presente revisão teve como objetivo descrever as contribuições de estudos que avaliaram os níveis de TNF-α e o polimorfismo -308 G/A em pacientes com DTM. Esse estudo enfatizou a importância de um tratamento mais completo envolvendo os inibidores do TNF-α que podem potencialmente reduzir a inflamação e a dor, contribuindo para melhorar a qualidade de vida do paciente. Métodos: As pesquisas foram realizadas nas bases de dados MEDLINE/PubMed, Cochrane Library e Web of Science, em busca de estudos de caso-controle publicados até setembro de 2020 que avaliassem os níveis de TNF-α e seu polimorfismo -308 G/A nos pacientes com DTM e em controles saudáveis. Resultados: Seis estudos de caso-controle foram identificados, com um total de 398 pacientes com DTM, e a idade variou de 12 a 78 anos. O grupo controle consistiu de 149 indivíduos e sua idade variou, aproximadamente, de 18 a 47 anos. O sexo feminino foi predominante. A maioria das pesquisas encontrou níveis elevados de TNF-α nos pacientes, em comparação com os controles. Um estudo encontrou uma associação positiva entre o genótipo GA e o desenvolvimento de DTM. Conclusão: A maioria dos pacientes com DTM demonstrou predisposição a uma maior produção de TNF-α, e isso poderia ser explicado pela presença do polimorfismo -308 G/A.

PAX7 gene polymorphism in muscular temporomandibular disorders as potentially related to muscle stem cells.

BACKGROUND: Temporomandibular disorders (TMD) are a group of painful and debilitating disorders, involving the masticatory muscles and/or the temporomandibular joint (TMJ). Chronic TMD pain can be associated with genetic changes in the key muscle development genes. OBJECTIVE: To evaluate the association between polymorphisms in the PAX7 (paired box 7) gene and masticatory myalgia in patients with temporomandibular disorders (TMD). MATERIALS AND METHODS: This is a case-control study. Patients with TMD were divided into two groups: (a) presence of muscular TMD (n = 122) and (b) absence of muscular TMD (n = 49). Genomic DNA was obtained from saliva samples from all participants to allow for genotyping single nucleotide polymorphisms in PAX7 (rs766325 and rs6659735). Over-representation of alleles was tested using chi-square or Fisher's exact tests. Values of p < 0.05 were considered to be statistically significant. RESULTS: Individuals without muscular TMD were less likely to have the PAX7 rs6659735 GG genotype (p = 0.03). No associations were found for PAX7 rs766325. CONCLUSIONS: Alterations in PAX7 may influence muscular pathophysiology and individuals with TMD and the rs6659735 homozygous genotype (GG) are seemingly associated with muscular involvement of the disorder. No associations were found in the region rs766325.

COL5A1 RS12722 Is Associated with Temporomandibular Joint Anterior Disc Displacement without Reduction in Polish Caucasians.

Numerous reports describe the association between the single-nucleotide polymorphism (SNP) rs12722 and rs13946 in the COL5A1 gene and injuries, such as Achilles tendon pathology, anterior cruciate ligament (ACL) injuries, and tennis elbow. Hence, there were no studies investigating COL5A1 and temporomandibular joint (TMJ) pathology. The aim of this study is to evaluate the relationship between COL5A1 rs12722 and rs13946 SNPs and TMJ articular disc displacement without reduction (ADDwoR). In this case-control study, the study group consisted of 124 Caucasian patients of both sexes. Each patient had a history of ADDwoR no more than 3 months prior. The control group comprised 126 patients with no signs of TMD according to DC/TMD. Genotyping of the selected SNPs was performed by real-time PCR using TaqMan probes. The significance of the differences in the distribution of genotypes was analyzed using Pearson's chi-square test. Logistic regression modeling was performed to analyze the influence of the 164 investigated SNPs on ADDwoR. The COL5A1 marker rs12722 turned out to be statistically significant (p-value = 0.0119), implying that there is a difference in the frequencies of TMJ ADDwoR. The distribution of rs12722 SNPs in the study group TT(66), CC(27), CT(31) vs. control group TT(45), CC(26), CT(51) indicates that patients with CT had an almost 2.4 times higher likelihood of ADDwoR (OR = 2.41) than those with reference TT (OR = 1), while rs13946 genotypes were shown to be insignificant, with a p-value of 0.1713. The COL5A1 rs12722 polymorphism is a risk factor for ADDwoR in the Polish Caucasian population.

Microarray Analysis of Differential Gene Expression Between Traumatic Temporomandibular Joint Fibrous and Bony Ankylosis in a Sheep Model.

BACKGROUND The type of traumatic temporomandibular joint (TMJ) ankylosis depends on the degree of severity of TMJ trauma. Here, we performed comprehensive differential molecular profiling between TMJ fibrous and bony ankylosis. MATERIAL AND METHODS Six sheep were used and a bilateral different degree of TMJ trauma was performed to induce fibrous ankylosis in one side and bony ankylosis in the other side. The ankylosed calluses were harvested at days 14 and 28 postoperatively and analyzed by Affymetrix OviGene-1_0-ST microarrays. DAVID was used to perform the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis for the different expression genes (DEGs). The DEGs were also typed into protein-protein interaction (PPI) networks to get the interaction data. Ten DEGs, including 7 hub genes from PPI analysis, were confirmed by real-time PCR. RESULTS We found 90 and 323 DEGs at least 2-fold at days 14 and 28, respectively. At day 14, bony ankylosis showed upregulated DEGs, such as TLR8, SYK, NFKBIA, PTPRC, CD86, ITGAM, and ITGAL, indicating a stronger immune and inflammatory response and cell adhesion, while genes associated with anti-adhesion (PRG4) and inhibition of osteoblast differentiation (SFRP1) had higher expression in fibrous ankylosis. At day 28, bony ankylosis showed increased biological process related to new bone formation, while fibrous ankylosis was characterized by a prolonged immune and inflammatory reaction. CONCLUSIONS This study provides a differential gene expression profile between TMJ fibrous and bony ankylosis. Further study of these key genes may provide new ideas for future treatment of TMJ bony ankylosis.

COL12A1 Single Nucleotide Polymorphisms rs240736 and rs970547 Are Not Associated with Temporomandibular Joint Disc Displacement without Reduction.

Temporomandibular disorders (TMDs) may affect up to 25% of the population, with almost 70% of these TMD cases developing malpositioning of the disc over time in what is known as internal derangement (ID). Despite significant efforts, the molecular mechanism underlying disease progression is not yet very well known. In this study, the role of COL12A1 rs970547 and rs240736 polymorphisms as potential genetic factors regulating ID was investigated. The study included 124 Caucasian patients of both sexes after disc displacement without reduction (DDwoR) in either one or two temporomandibular joints (TMJs), either of which meet the criteria for this condition. All patients underwent clinical examination and 3D digital imaging. The COL12A1 rs970547 and rs240736 polymorphisms were evaluated. There were no statistically significant differences in the chi-square test between the study group and healthy controls. The examined COL12A1 rs240736 and rs970547 polymorphisms do not contribute to DDwoR in Polish Caucasians.