Causal effects of autoimmune diseases on temporomandibular disorders and the mediating pathways: a Mendelian randomization study.

Background: The role of autoimmune diseases (ADs) in temporomandibular disorders (TMDs) has been emphasized in observational studies. However, whether the causation exists is unclear, and controversy remains about which specific disorder is destructive in TMDs. This Mendelian randomization (MR) study aims to estimate the causal effect of common ADs on TMDs. Methods: Genetic data from published genome-wide association studies for fourteen common ADs, specifically multiple sclerosis (MS, N = 15,283), ankylosing spondylitis (AS, N = 22,647), asthma (N = 408,422), celiac disease (N = 15,283), Graves' disease (N = 458,620), Hashimoto thyroiditis (N = 395,640), primary biliary cirrhosis (PBC, N = 11,375), primary sclerosing cholangitis (PSC, N = 14,890), psoriasis vulgaris (N = 483,174), rheumatoid arthritis (RA, N = 417,256), systemic lupus erythematosus (SLE, N = 23,210), Type 1 diabetes (T1D, N = 520,580), inflammatory bowel disease (IBD, N = 34,652), and Sjogren's syndrome (SS, N = 407,746) were collected. Additionally, the latest summary-level data for TMDs (N = 228,812) were extracted from the FinnGen database. The overall effects of each immune traits were assessed via inverse-variance weighted (IVW), weighted median, and MR-Egger methods, and performed extensive sensitivity analyses. Finally, 731 immune cell phenotypes (N = 3,757) were analyzed for their mediating role in the significant causality. Results: Univariable MR analyses revealed that genetically predicted RA (IVW OR: 1.12, 95% CI: 1.05-1.19, p < 0.001) and MS (IVW OR: 1.06, 95% CI: 1.03-1.10, p = 0.001) were associated with increased risk of TMDs. Two out of 731 immune cell phenotypes were identified as causal mediators in the associations of RA with TMDs, including "CD25++ CD8+ T cell % CD8+ T cell" (mediation proportion: 6.2%) and "CD3 on activated CD4 regulatory T cell" (5.4%). Additionally, "CD127 on granulocyte" mediated 10.6% of the total effect of MS on TMDs. No reverse directions, heterogeneity, and pleiotropy were detected in the analyses (p > 0.05). Conclusion: This MR study provides new evidence regarding the causal impact of genetic predisposition to RA or MS on the increased risk of TMDs, potentially mediated by the modulation of immune cells. These findings highlight the importance for clinicians to pay more attention to patients with RA or MS when consulting for temporomandibular discomfort. The mediating role of specific immune cells is proposed but needs further investigation.

Genetic change investigation in DOCK1 gene in an Iranian family with sign and symptoms of temporomandibular joint disorder (TMD).

OBJECTIVES: Temporomandibular joint disorder (TMD) is a complex condition with pain and dysfunction in the temporomandibular joint and related muscles. Scientific evidence indicates both genetic and environmental factors play a crucial role in TMD. In this study, we aimed to discover the genetic changes in individuals from 4 generations of an Iranian family with signs and symptoms of TMD and malocclusion Class III. MATERIALS AND METHODS: Whole Exome Sequencing (WES) was performed in 4 patients (IV-8, IV-9, V-4, and V-6) with TMD according to (DC/TMD), along with skeletal Class III malocclusion. Then, PCR sequencing was performed on 23 family members to confirm the WES. RESULTS: In the present study, WES results analysis detected 6 heterozygous non-synonymous Single Nucleotide Variants (SNVs) in 5 genes, including CRLF3, DNAH17, DOCK1, SEPT9, and VWDE. A heterozygous variant, c.2012T > A (p.F671Y), in Exon 20 of the DOCK1 (NM_001290223.2) gene was identified. Then, this variant was investigated in 19 other members of the same family. PCR-Sequencing results showed that 7/19 had heterozygous TA genotype, all of whom were accompanied by malocclusion and TMD symptoms and 12/19 individuals had homozygous TT genotype, 9 of whom had no temporomandibular joint problems or malocclusion. The remaining 3 showed mild TMD clinical symptoms. The 5 other non-synonymous SNVs of CRLF3, DNAH17, SEPT9, and VWDE were not considered plausible candidates for TMD. CONCLUSIONS: The present study identified a heterozygous nonsynonymous c.2012T > A (p.F671Y) variant of the DOCK1 gene is significantly associated with skeletal class III malocclusion, TMD, and its severity in affected individuals in the Iranian pedigree. CLINICAL RELEVANCE: The role of genetic factors in the development of TMD has been described. The present study identified a nonsynonymous variant of the DOCK1 gene as a candidate for TMD and skeletal class III malocclusion in affected individuals in the Iranian pedigree.

The association between genetic factors and temporomandibular disorders: A systematic literature review.

OBJECTIVE: This study aimed to investigate the correlation between genetic factors and the occurrence and progression of temporomandibular disorders (TMDs) using a comprehensive review and meta-analysis. DESIGN: A comprehensive search was conducted using the ScienceDirect, PubMed, Cochrane Library, Dimensions, and Emerald databases. A reviewer selected the study using modified PICO criteria, considering human subjects with TMDs, comparing different genetic factors among TMD and non-TMD patients, and reporting TMD signs and symptoms as outcomes. The methodological standards of the eligible papers were assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Non-randomized Experimental Investigations. Information was collected methodically and examined. RESULTS: The electronic database search yielded 851 articles, 19 of which were included in this study. The data analysis showed a significant influence of genetic factors, such as polymorphisms and gene differences, on the development of TMD signs and symptoms, such as myofascial pain, chronic pain, and disc displacement. In addition, gene polymorphism significantly influenced TMD development, with an odds ratio of 2.46 (1.93-3.14) and p of 0.00001. CONCLUSIONS: Genetic factors significantly influenced TMD signs and symptoms, and genetic polymorphisms significantly influenced TMD onset and progression. Further research should be conducted in diverse settings with larger sample sizes to verify and validate these findings.

Exploring the causal effects of sleep characteristics on TMD-related pain: a two-sample Mendelian randomization study.

OBJECTIVES: The study was to explore the causal effects of sleep characteristics on temporomandibular disorder (TMD)-related pain using Mendelian randomization (MR) analysis. MATERIALS AND METHODS: Five sleep characteristics (short sleep, insomnia, chronotype, snoring, sleep apnea) were designated as exposure factors. Data were obtained from previous publicized genome-wide association studies and single nucleotide polymorphisms (SNPs) strongly associated with them were utilized as instrumental variables (IVs). TMD-related pain was designed as outcome variable and sourced from the FinnGens database. MR analysis was employed to explore the causal effects of the five sleep characteristics on TMD-related pain. The causal effect was analyzed using the inverse variance-weighted (IVW), weighted median, and MR-Egger methods. Subsequently, sensitivity analyses were conducted using Cochran's Q tests, funnel plots, leave-one-out analyses, and MR-Egger intercept tests. RESULTS: A causal effect of short sleep on TMD-related pain was revealed by IVW (OR: 1.60, 95% CI: 1.06-2.41, P = 0.026). No causal relationship was identified between other sleep characteristics (insomnia, chronotype, snoring, sleep apnea) and TMD-related pain. CONCLUSIONS: Our study suggests that short sleep may increase the risk of TMD-related pain, while there was no causal relationship between other sleep characteristics and TMD-related pain. Further studies are warranted to deepen and definitively clarify their relationship. CLINICAL RELEVANCE: These findings reveal that the short sleep may be a risk factor of TMD-related pain and highlight the potential therapeutical effect of extending sleep time on alleviating TMD-related pain.

YAP promotes the early development of temporomandibular joint bony ankylosis by regulating mesenchymal stem cell function.

To explore the role of YAP, a key effector of the Hippo pathway, in temporomandibular joint (TMJ) ankylosis. The temporal and spatial expression of YAP was detected via immunohistochemistry and multiplex immunohistochemistry on postoperative Days 1, 4, 7, 9, 11, 14 and 28 in a sheep model. Isolated mesenchymal stem cells (MSCs) from samples of the Day 14. The relative mRNA expression of YAP was examined before and after the osteogenic induction of MSCs. A YAP-silenced MSC model was constructed, and the effect of YAP knockdown on MSC function was examined. YAP is expressed in the nucleus of the key sites that determine the ankylosis formation, indicating that YAP is activated in a physiological state. The expression of YAP increased gradually over time. Moreover, the number of cells coexpressing of RUNX2 and YAP-with the osteogenic active zone labelled by RUNX2-tended to increase after Day 9. After the osteogenic induction of MSCs, the expression of YAP increased. After silencing YAP, the osteogenic, proliferative and migratory abilities of the MSCs were inhibited. YAP is involved in the early development of TMJ bony ankylosis. Inhibition of YAP using shRNA might be a promising way to prevent or treat TMJ ankylosis.

Long-term haplodeficency of DSPP causes temporomandibular joint osteoarthritis in mice.

BACKGROUND: Extracellular matrix (ECM) protein malfunction or defect may lead to temporomandibular joint osteoarthritis (TMJ OA). Dentin sialophophoprotein (DSPP) is a mandibular condylar cartilage ECM protein, and its deletion impacted cell proliferation and other extracellular matrix alterations of postnatal condylar cartilage. However, it remains unclear if long-term loss of function of DSPP leads to TMJ OA. The study aimed to test the hypothesis that long-term haploinsufficiency of DSPP causes TMJ OA. MATERIALS AND METHODS: To determine whether Dspp+/- mice exhibit TMJ OA but no severe tooth defects, mandibles of wild-type (WT), Dspp+/-, and Dspp homozygous (Dspp-/-) mice were analyzed by Micro-computed tomography (micro-CT). To characterize the progression and possible mechanisms of osteoarthritic degeneration over time in Dspp+/- mice over time, condyles of Dspp+/- and WT mice were analyzed radiologically, histologically, and immunohistochemically. RESULTS: Micro-CT and histomorphometric analyses revealed that Dspp+/- and Dspp-/- mice had significantly lower subchondral bone mass, bone volume fraction, bone mineral density, and trabecular thickness compared to WT mice at 12 months. Interestingly, in contrast to Dspp-/- mice which exhibited tooth loss, Dspp+/- mice had minor tooth defects. RNA sequencing data showed that haplodeficency of DSPP affects the biological process of ossification and osteoclast differentiation. Additionally, histological analysis showed that Dspp+/- mice had condylar cartilage fissures, reduced cartilage thickness, decreased articular cell numbers and severe subchondral bone cavities, and with signs that were exaggerated with age. Radiographic data showed an increase in subchondral osteoporosis up to 18 months and osteophyte formation at 21 months. Moreover, Dspp+/- mice showed increased distribution of osteoclasts in the subchondral bone and increased expression of MMP2, IL-6, FN-1, and TLR4 in the mandibular condylar cartilage. CONCLUSIONS: Dspp+/- mice exhibit TMJ OA in a time-dependent manner, with lesions in the mandibular condyle attributed to hypomineralization of subchondral bone and breakdown of the mandibular condylar cartilage, accompanied by upregulation of inflammatory markers.

Construction of the chronic temporomandibular disorder patients: the association between neural and psychological pathways.

Chronic temporomandibular disorder (cTMD) as a term based on the diagnostic criteria for temporomandibular disorders (DC/TMD) classification refers, in this paper, to the condition listed that has a non-mechanical association without any obvious organic cause. Specifically, this is the condition that falls under the International Classification of Diseases 11th revision (ICD-11) classification of chronic primary and chronic secondary pains. This implies that there is increased responsiveness of nociceptive neurons in the central nervous system, a phenomenon known as central sensitisation. cTMD patients may have their beginning with genetic susceptibility to pain. Although no single gene is exclusively linked to cTMD, various genes associated with nervous and musculoskeletal systems are believed to play a role. Environmental triggers and epigenetic changes are also thought to contribute to cTMD development. The biopsychosocial model emphasises the need to comprehensively address biological, psychological and social factors in cTMD assessment and management. In this study, we leverage the cyclic causation framework within the biopsychosocial model to illuminate the intricate interplay between biological and psychosocial factors in the context of cTMD. The conceptualisation of cTMD involves the dynamic evolution of genetic predispositions, influenced by life events and other biological susceptibilities. These factors collectively contribute to the emergence of nociplastic changes, ultimately manifesting as the distinctive features observed in individuals afflicted with cTMD.

Integration of metabolomics and transcriptomics provides insights into the molecular mechanism of temporomandibular joint osteoarthritis.

The deficiency of clinically specific biomarkers has made it difficult to achieve an accurate diagnosis of temporomandibular joint osteoarthritis (TMJ-OA) and the insufficient comprehension of the pathogenesis of the pathogenesis of TMJ-OA has posed challenges in advancing therapeutic measures. The combined use of metabolomics and transcriptomics technologies presents a highly effective method for identifying vital metabolic pathways and key genes in TMJ-OA patients. In this study, an analysis of synovial fluid untargeted metabolomics of 6 TMJ-OA groups and 6 temporomandibular joint reducible anterior disc displacement (TMJ-DD) groups was conducted using liquid and gas chromatography mass spectrometry (LC/GC-MS). The differential metabolites (DMs) between TMJ-OA and TMJ-DD groups were analyzed through multivariate analysis. Meanwhile, a transcriptomic dataset (GSE205389) was obtained from the GEO database to analyze the differential metabolism-related genes (DE-MTGs) between TMJ-OA and TMJ-DD groups. Finally, an integrated analysis of DMs and DE-MTGs was carried out to investigate the molecular mechanisms associated with TMJ-OA. The analysis revealed significant differences in the levels of 46 DMs between TMJ-OA and TMJ-DD groups, of which 3 metabolites (L-carnitine, taurine, and adenosine) were identified as potential biomarkers for TMJ-OA. Collectively, differential expression analysis identified 20 DE-MTGs. Furthermore, the integration of metabolomics and transcriptomics analysis revealed that the tricarboxylic acid (TCA) cycle, alanine, aspartate and glutamate metabolism, ferroptosis were significantly enriched. This study provides valuable insights into the metabolic abnormalities and associated pathogenic mechanisms, improving our understanding of TMJOA etiopathogenesis and facilitating potential target screening for therapeutic intervention.

Tenosynovial giant cell tumor: case report and molecular investigation.

Tenosynovial giant cell tumor is a benign neoplasm arising from the synovium of joints, including the temporomandibular joint (TMJ). Despite its benign nature, these tumors may exhibit aggressive behavior. A 57-year-old woman with a swollen, hardened area in the left TMJ was referred to the university´s clinic. The diagnosis of tenosynovial giant cell tumor was made based on the presence of hyperplastic synovial lining containing mononuclear and giant cells, hemorrhagic areas, hemosiderin deposits, and calcification foci in the biopsy. A low condylectomy was performed, and histopathologic analysis of the surgical piece upheld the diagnosis. Due to histopathologic resemblance with other giant cell-rich lesions (giant cell granuloma of the jaws, brown tumor of hyperparathyroidism, and non-ossifying fibroma) for which signature mutations are known, mutational analysis of KRAS, FGFR1, and TRPV4 genes was conducted. The results revealed wild-type sequences for all the mutations tested, thereby supporting the diagnosis of tenosynovial giant cell tumor.

DDIT3 aggravates TMJOA cartilage degradation via Nrf2/HO-1/NLRP3-mediated autophagy.

OBJECTIVE: DNA damage-inducible transcript 3 (DDIT3), as a downstream transcription factor of endoplasmic reticulum stress, is reported to regulate chondrogenic differentiation under physiological and pathological state. However, the specific involvement of DDIT3 in the degradation of condylar cartilage of temporomandibular joint osteoarthritis (TMJOA) is unclarified. DESIGN: The expression patterns of DDIT3 in condylar cartilage from monosodium iodoacetate-induced TMJOA mice were examined to uncover the potential role of DDIT3 in TMJOA. The Ddit3 knockout (Ddit3-/-) mice and their wildtype littermates (Ddit3+/+) were used to clarify the effect of DDIT3 on cartilage degradation. Primary condylar chondrocytes and ATDC5 cells were applied to explore the mechanisms of DDIT3 on autophagy and extracellular matrix (ECM) degradation in chondrocytes. The autophagy inhibitor chloroquine (CQ) was used to determine the effect of DDIT3-inhibited autophagy in vivo. RESULTS: DDIT3 were highly expressed in condylar cartilage from TMJOA mice. Ddit3 knockout alleviated condylar cartilage degradation and subchondral bone loss, compared with their wildtype littermates. In vitro study demonstrated that DDIT3 exacerbated ECM degradation in chondrocytes induced by TNF-α through inhibiting autophagy. The intraperitoneal injection of CQ further confirmed that Ddit3 knockout alleviated cartilage degradation in TMJOA through activating autophagy in vivo. CONCLUSIONS: Our findings identified the crucial role of DDIT3-inhibited autophagy in condylar cartilage degradation during the development of TMJOA.

Genetic influence on treatment outcomes in patients with pain-related temporomandibular disorders.

BACKGROUND: Single nucleotide polymorphisms (SNPs) may influence pain susceptibility and impact treatment response in pain-related temporomandibular disorders (TMDp). OBJECTIVE: Explore the role of COMT (rs4646310, rs6269, rs4818, rs4680) and OPRM1 (rs1799971) genotypes in regulating treatment response. METHODS: Sixty TMDp patients (55 females and 5 males), diagnosed with the Diagnostic Criteria for TMD (DC/TMD), underwent standardised treatment (information and education, home physical therapy, occlusal splint) for 6 months. Treatment outcomes included: pain intensity, pain-free mouth opening, jaw functional limitation, depression, and anxiety. Genotyping for COMT and OPRM1 SNPs was performed using DNA from buccal mucosa swabs and TaqMan assays. Statistical analysis was carried out to compare the changes in treatment outcomes and the influence of genotypes on treatment response. RESULTS: Significantly less pain reduction was observed in minor allele carriers of rs4646310, and rs4680 compared to dominant homozygous (p < .025). Minor allele carriers of rs1799971 and rs4646310 demonstrated worsening in pain-free mouth opening while dominant homozygous exhibited improvement (p < .025). Significantly less anxiety reduction was observed in minor allele carriers of rs4646310 compared to dominant homozygous (p = .003). Of the all variables assessed in the regression model, carrying a minor allele of rs1799971 predicted a poorer treatment response considering pain-free mouth opening while carrying a minor allele of rs4646310 predicted less pain and less anxiety reduction. CONCLUSION: Our findings indicate that certain SNP variants of the COMT and OPRM1 genes were associated with poorer treatment response and may therefore play a significant role in the classification of TMDp patients. Also, assessment of patient genotype could potentially aid in predicting treatment response.

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.