Wnt signalling in oral and maxillofacial diseases.

Wnts include more than 19 types of secreted glycoproteins that are involved in a wide range of pathological processes in oral and maxillofacial diseases. The transmission of Wnt signalling from the extracellular matrix into the nucleus includes canonical pathways and noncanonical pathways, which play an important role in tooth development, alveolar bone regeneration, and related diseases. In recent years, with the in-depth study of Wnt signalling in oral and maxillofacial-related diseases, many new conclusions and perspectives have been reached, and there are also some controversies. This article aims to summarise the roles of Wnt signalling in various oral diseases, including periodontitis, dental pulp disease, jaw disease, cleft palate, and abnormal tooth development, to provide researchers with a better and more comprehensive understanding of Wnts in oral and maxillofacial diseases.

BRD4 inhibition alleviates mechanical stress-induced TMJ OA-like pathological changes and attenuates TREM1-mediated inflammatory response.

The aim of this paper was to investigate the protective effects of bromodomain containing 4 (BRD4) inhibition on the temporomandibular joint osteoarthritis (TMJ OA) induced by compressive mechanical stress and to explore the underlying mechanism. In vivo, a rat model of TMJ compressive loading device was used and BRD4 inhibitor was injected into the TMJ region. HE staining and micro-CT analysis were used for histological and radiographic assessment. Immunohistochemistry and qPCR were performed to detect inflammatory cytokines expressions. High-throughput ChIP-sequencing screening was performed to compare the BRD4 and H3K27ac binding patterns between condylar cartilage from control and mechanical force groups. In vitro, the mandibular condylar chondrocytes were treated with IL-1ß. Small Interference RNA (siRNA) infection was used to silencing BRD4 or TREM1. qPCR was performed to detect inflammatory cytokines expressions. Our study showed that BRD4 inhibition can alleviate the thinning of condylar cartilage and subchondral bone resorption, as well as decrease the inflammatory factors expression both in vivo and in vitro. ChIP-seq analysis showed that BRD4 was more enriched in the promoter region of genes related to the stress and inflammatory pathways under mechanical stress in vivo. Trem1, a pro-inflammatory gene, was screened out from the overlapped BRD4 and H3K27ac increased binding sites, and Trem1 mRNA was found to be regulated by BRD4 inhibition both in vivo and in vitro. TREM1 inhibition reduced the expression of inflammatory factors induced by IL-1ß in vitro. In summary, we concluded that BRD4 inhibition can protect TMJ OA-like pathological changes induced by mechanical stress and attenuate TREM1-mediated inflammatory response.

The many faces of genetic contributions to temporomandibular joint disorder: An updated review.

OBJECTIVES: The aim was to review the literature regarding genetic contributions to temporomandibular joint disorder (TMD) after our 2008 publication. SETTING AND SAMPLE POPULATION: Literature review. MATERIAL AND METHODS: PubMed and MEDLINE were used to obtain literature in any language regarding genes and TMD, using the keywords "temporomandibular joint disorder" and "temporomandibular joint dysfunction" for studies published from 2009 to 2017. RESULTS: In our search, 274 studies were found. We excluded 76 studies from animal models, 22 studies that were in vitro and 120 reports that were not cohort or case-control studies. Of the 274 results, 56 articles were selected for this review. Genes that are suggested to contribute to TMD included the ones related to disc and bone alterations as well as pain sensation. CONCLUSION: Currently, no evidence of associated genetic variants, which can determine the development of TMD in individuals, could be translated to novel clinical management and public health strategies for patients suffering from TMD.

Estradiol upregulates voltage-gated sodium channel 1.7 in trigeminal ganglion contributing to hyperalgesia of inflamed TMJ.

BACKGROUND: Temporomandibular disorders (TMDs) have the highest prevalence in women of reproductive age. The role of estrogen in TMDs and especially in TMDs related pain is not fully elucidated. Voltage-gated sodium channel 1.7 (Nav1.7) plays a prominent role in pain perception and Nav1.7 in trigeminal ganglion (TG) is involved in the hyperalgesia of inflamed Temporomandibular joint (TMJ). Whether estrogen could upregulate trigeminal ganglionic Nav1.7 expression to enhance hyperalgesia of inflamed TMJ remains to be explored. METHODS: Estrous cycle and plasma levels of 17ß-estradiol in female rats were evaluated with vaginal smear and enzyme linked immunosorbent assay, respectively. Female rats were ovariectomized and treated with 17ß-estradiol at 0 µg, 20 µg and 80 µg, respectively, for 10 days. TMJ inflammation was induced using complete Freund's adjuvant. Head withdrawal thresholds and food intake were measured to evaluate the TMJ nociceptive responses. The expression of Nav1.7 in TG was examined using real-time PCR and western blot. The activity of Nav1.7 promoter was examined using luciferase reporter assay. The locations of estrogen receptors (ERα and ERß), the G protein coupled estrogen receptor (GPR30), and Nav1.7 in TG were examined using immunohistofluorescence. RESULTS: Upregulation of Nav1.7 in TG and decrease in head withdrawal threshold were observed with the highest plasma 17ß-estradiol in the proestrus of female rats. Ovariectomized rats treated with 80 µg 17ß-estradiol showed upregulation of Nav1.7 in TG and decrease in head withdrawal threshold as compared with that of the control or ovariectomized rats treated with 0 µg or 20 µg. Moreover, 17ß-estradiol dose-dependently potentiated TMJ inflammation-induced upregulation of Nav1.7 in TG and also enhanced TMJ inflammation-induced decrease of head withdrawal threshold in ovariectomized rats. In addition, the estrogen receptor antagonist, ICI 182,780, partially blocked the 17ß-estradiol effect on Nav1.7 expression and head withdrawal threshold in ovariectomized rats. ERα and ERß, but not GPR30, were mostly co-localized with Nav1.7 in neurons in TG. In the nerve growth factor-induced and ERα-transfected PC12 cells, 17ß-estradiol dose-dependently enhanced Nav1.7 promoter activity, whereas mutations of the estrogen response element at -1269/-1282 and -1214/-1227 in the promoter completely abolished its effect on the promoter activity. CONCLUSION: Estradiol could upregulate trigeminal ganglionic Nav1.7 expression to contribute to hyperalgesia of inflamed TMJ.

Autism spectrum disorder and other neurobehavioural comorbidities in rare disorders of the Ras/MAPK pathway.

AIM: To investigate the cognitive and behavioural phenotype in rare disorders of the Ras/MAPK pathway, namely Noonan, cardiofaciocutaneous (CFC), and Costello syndromes, particularly prevalence of autism spectrum disorder (ASD) and attention-deficit-hyperactivity disorder (ADHD). METHOD: Fifty children were recruited over 10 months through the regional genetics service and advertisements. A range of parent, child, and observational measures were administered including Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Scale. RESULTS: Using the Collaborative Programme for Excellence in Autism criteria, 12 out of 40 children with Noonan syndrome (30%) showed ASD, and 12 out of 40 (30%) with partial ASD features and 16 out of 40 (40%) showed non-ASD. The Noonan syndrome ASD group showed male dominance in a ratio of 5:1. In the CFC group, eight out of nine children met the criteria for ASD, with equal sex distribution. Additionally 19 out of 40 (48%) of the Noonan syndrome group and eight out of nine (88.9%) of the CFC group scored met clinical criteria for ADHD. Only one child was in the Costello syndrome group. INTERPRETATION: This is the first systematic study to suggest a high prevalence of ASD in Noonan and CFC syndromes, and thus offers crucial evidence to support the importance of the Ras/MAPK pathway in the aetiology of ASD. Limitations include the inevitable possibility of a sampling bias in a rare disorder study of this kind.

Early-lethal Costello syndrome due to rare HRAS Tandem Base substitution (c.35_36GC>AA; p.G12E)-associated pulmonary vascular disease.

Costello syndrome is a rare, autosomal-dominant syndrome caused by activating missense mutations in the Harvey rat sarcoma viral oncogene homolog (HRAS), most often p.G12S. Several rare mutations have consistently been associated with a more severe phenotype that is often lethal in infancy. Cause of death is most often respiratory failure, with hypertrophic cardiomyopathy playing a significant role in morbidity. Impaired fibroblast elastogenesis is thought to contribute to the Costello phenotype, but reports of histologic evidence of disordered elastogenesis at autopsy are limited. We report a patient with Costello syndrome due to a rare tandem base substitution (c.35_36GC>AA) resulting in the p.G12E missense change. The proband died at the age of 3 months from respiratory failure, with minimal evidence of cardiomyopathy. The autopsy disclosed pulmonary vascular dysplasia affecting small arteries and veins associated with abnormal elastin distribution in tortuous dilated arteries and veins, with nonuniform wall thickness and semiobstructive lesions at artery branch points typical of early pulmonary hypertensive vascular disease. Elastic fibers in the dermis were abnormally short and fragmented. This case suggests that disordered elastogenesis in the pulmonary vasculature and undiagnosed (or underdiagnosed) pulmonary hypertension may contribute to morbidity in patients with Costello syndrome.

Nonsynonimous mutation of catechol-O-methyl-transferase (COMT) gene in a patient with temporomandibular disorder.

We report a case of temporomandibular disorder patient with disc displacement without reduction, myofascial pain, limited opening and a novel, never described, nonsynonimous mutation of catechol-O-methyl-transferase (COMT) gene. COMT is one of the enzymes that metabolizes catecholamines, thereby acting as a key modulator of dopaminergic and adrenergic/noradrenergic neurotransmissions, which play a key role in pain modulation. This novel mutation, p.R58S, changed a codon (58 from arginine to serine) in the COMT protein. The introduction of a serine residue in a highly organised secondary structure, in critical regions of the protein, results in a structural alteration. Therefore, we speculate an influence of the mutation on the high pain sensitivity of the patient.

Pathophysiology of TMD pain--basic mechanisms and their implications for pharmacotherapy.

This article discusses the pathophysiology of temporomandibular disorders (TMD)-related pain and its treatment with analgesic drugs. Temporomandibular disorders are comprised of a group of conditions that result in temporomandibular joint pain (arthralgia, arthritis) and/or masticatory muscle pain (myofascial TMD). In at least some patients with TMD, a peripheral mechanism contributes to this pain. However, there is often a poor correlation between the severity of TMD-related pain complaints and evidence of definitive tissue pathology. This has led to the concept that pain in some patients with TMD may result from altered central nervous system pain processing and further that this altered pain processing may be attributable to specific genes that are heritable. Psychosocial stressors are also thought to contribute to the development of TMD-related pain, particularly masticatory muscle pain. Finally, substantially more women suffer from TMD than men. Although there are arguably multiple reasons for sex-related differences in the prevalence of TMD, one candidate for the increased occurrence of this disorder in women has been suggested to be the female sex hormone oestrogen. Analgesic drugs are an integral part of the primary treatment for TMD-related pain and dysfunction with more that 90% of treatment recommendations involving use of medications. The most commonly used agents include non-steroidal anti-inflammatory drugs, corticosteroids, muscle relaxants, anxiolytics, opiates and tricyclic antidepressants, however, evidence in support of the effectiveness of these drugs is lacking. Continued research into the pathophysiology of TMD-related pain and the effectiveness of analgesic treatments for this pain is required.

[Costeff syndrome: a syndrome that was described in Israel and the responsible gene discovered by an Israeli doctor].

Costeff syndrome or 3-methylglutaconic aciduria type 3, was described by a group of Israeli doctors in 1989. Since then more than 40 patients were described. Most of the patients are of Iraqi-Jewish origin. The clinical abnormalities are bilateral optic atrophy, extrapyramidal signs, spasticity ataxia, dysarthria and mild cognitive deficit. Recently, the gene responsible for this disorder, OPA3 gene was identified. This gene was also discovered by an Israeli doctor. This is a case history of a patient with Costeff syndrome presenting the characteristics of this syndrome and the gene that causes this disease.

Mirror image condylar hyperplasia in two siblings.

A Hispanic family with an unusual clinical and radiological pattern of condylar hyperplasia is presented. Mirror images of condylar hyperplasia, malocclusion of teeth, and shift of midline of the mandible were seen in two brothers. The father had a similar abnormality of his left mandibular condyle. The condylar hyperplasia in this family indicates that mandibular condylar hyperplasias could be genetic in origin, possibly Y-linked or autosomal dominant.

Possible association of temporomandibular joint pain and dysfunction with a polymorphism in the serotonin transporter gene.

The purpose of this study was to evaluate the relationship between temporomandibular joint pain and dysfunction and serotonin transporter (5-HTT) gene polymorphism. Forty-eight patients with temporomandibular joint pain and 111 healthy control subjects were examined. The results for the patients and control subjects were not significantly different (P >.05). The analysis of genotype distribution (homozygous for STin 2.10 genotypes of the variable-number tandem-repeat polymorphism) showed significant differences between the patients and control subjects (P =.003). ST 2.10 allele was more frequent in the patients with temporomandibular joint pain and dysfunction. In the control group, however, STin 2.12/12 genotype was significantly higher (P =.017). In the patients who were homozygous or heterozygous for variable-number tandem-repeat variants of 5-HTT STin 2.12 copies, the average scores of somatization and anger were significantly higher than those who were homozygous for STin 2.10 variant (P <.05). The patients who were homozygous for STin 2.10 genotype were also homozygous for "L" genotype (P =.019). However, this was not the condition in the control subjects. This study does not provide evidence to support the involvement of 5-HTT gene-linked polymorphic region in temporomandibular joint pain and dysfunction. Our findings indicated that only the presence of the homozygous STin 2.10 genotype of variable-number tandem-repeat is likely to play a substantial role in the genetic predisposition to temporomandibular joint pain and dysfunction and that the STin 2.12/12 genotype may have a protective role against temporomandibular joint pain and dysfunction.

[Dysplasia-dependent abnormalities of the temporomandibular joint]. / Displastikozavisimaia patologiia visochno-nizhnecheliustnogo sustava.

The purpose of this study was to reveal the relationship between temporomandibular joint (TMJ) dysfunction and dysplasia of connective tissue (DCT). This investigation included 53 (34 female and 19 male) patients with TMJ internal derangement (ID) and 53 controls; 24 patients with marked and 53 patients with mild dysfunction of this joint. The symptoms of DCT (such as scoliosis, general joint hypermorbility) and TMJ ID were revealed. Results of this study prove that DCT is one of etiological factors of TMJ ID. The relationship between type of ID and severity of DCT was revealed.

Myofascial TMD does not run in families.

This study tests whether facial pain or associated symptoms and disorders aggregates in first degree relatives of those with myofascial temporomandibular disorders (M/TMD). We randomly selected one first degree relative of 106 probands with a lifetime history of M/TMD and one first degree relative of 118 acquaintance control probands with no history of M/TMD. Relatives were directly interviewed about the lifetime occurrence of a broad range of painful and non-painful health conditions and symptoms. Analyses revealed that rates of facial pain, symptoms of TMDs, and a range of other musculoskeletal conditions were not significantly different in first degree relatives of M/TMD probands and first degree relatives of controls. In addition, proband descriptors of facial pain severity or disability did not significantly predict the likelihood of having a first degree relative with one or more TMD-related symptoms. These results indicate that M/TMD is not a familial disorder.

[Stomatologic implications of Turner syndrome II. Orthodontic disorders and some characteristics of the temporomandibular joint]. / A Turner-szindróma stomatológiai vonatkozásai II. Orthodontiai rendellenességek és a temporomandibularis ízület néhány jellemzöje.

Turner syndrome is a disease belonging to the group of chromosome disorders, which affect sexual chromosomes. The present study aims at analysing and describing orthodontic and TMI joint disorders in patients with Turner's syndrome, and comparing the results with those healthy controls. Data of 24 patients with Turner's syndrome as well as 24 healthy controls were collected and analysed. No significant alteration in TMI was found in any of the two groups. Both groups presented orthodontic anomalies, however, crowding was the most common anomaly in the control group, whereas in the case of patients with Turner's syndrome, other anomalies (protrusion, open bite, cross bite) could also be found more frequently.

Illness and injury among children of temporomandibular pain and dysfunction syndrome (TMPDS) patients.

This paper examines findings on illnesses and injuries among patients suffering from temporomandibular pain and dysfunction syndrome (TMPDS). Data from the longitudinal component of a case-control study of 151 TMPDS patients and 139 healthy controls were examined, focusing especially on the 31 cases and 41 controls with children. Patients are significantly more likely to report illnesses but not injuries among their children across 10 monthly interviews. The patients' excess in reporting of illnesses is not found for spouses or additional significant others. Overreporting does not appear to be due to illness attitudes or other discernible reporting biases, but may be partially attributable to higher rates of demoralization among the cases. Findings are discussed in view of hypotheses about familially transmitted vulnerability to pain and illness.

Myofascial pain dysfunction (MPD) syndrome in twins.

The Myofascial Pain Dysfunction Syndrome (MPD) was investigated in 94 twin pairs (21 male pairs and 73 female pairs), who had not been selected with respect to MPD. The frequency of past and/or present symptoms was found to be 10% in males and 27% in females. No differences between monozygous (identical) and dizygous (non-identical) female twins was found in pair-wise concordance rates, the concordance rate being higher than expected to occur by chance in both twin types. The findings are compatible with the view that environmental influences give rise to this specific stress-reaction pattern.