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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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Cheng, Xu, Wang, Zhao and Jiang.)

The underlying mechanisms and treatment of painful temporomandibular disorders (TMDs) are important but understudied topics in craniofacial research. As a group of musculoskeletal diseases, the onset of painful TMD is proved to be a result of disturbance of multiple systems. Recently, emerging evidence has revealed the involvement of neuroimmune interactions in painful TMD. Inflammatory factors play an important role in peripheral sensitization of temporomandibular joint (TMJ), and neurogenic inflammation in turn enhances TMJs dysfunction in TMD. Furthermore, centralized neuroimmune communications contribute to neuron excitability amplification, leading to pain sensitization, and is also responsible for chronic TMD pain and other CNS symptoms. Therapeutics targeting neuroimmune interactions may shed light on new approaches for treating TMD. In this review, we will discuss the role of neuroimmune interactions in the onset of painful TMD from the peripheral and centralized perspectives, and how understanding this mechanism could provide new treatment options. Insights into the neuroimmune interactions within TMJs and painful TMD would broaden the knowledge of mechanisms and treatments of this multifactorial disease., (©2021 Society for Leukocyte Biology.)

Aim: Inflammatory idiopathic myopathies (IIMs) are inflammatory processes affecting skeletal musculature and extramuscular organs. Temporomandibular disorders (TMD) involve jaw muscles and temporomandibular joint. The aim of this observational study was to investigate the prevalence of the main TMD symptoms and signs as well as oral implications in IIM patients. Methods: The study group included 54 patients (42 women and 12 men), 22 of whom affected by dermatomyositis (DM), 29 by polymyositis (PM) and 3 by inclusion body myositis (IBM). A group of 54 patients not affected by this disease, served as CG. Oral and TMD signs and symptoms were evaluated by means of a questionnaire and through clinical examination. Results: About oral symptoms, the study group complained more frequently dysgeusia, with loss of taste or unpleasant taste ( p <0.0001) and feeling of burning mouth (9.4% versus 0 controls). Xerostomia was more prevalent in the study group respect to the CG ( p <0.0001). Dysphagia was reported by 48.1% of IIM patients while was absent in CG ( p <0.0001). About oral signs, cheilitis ( p <0.05) and oral ulcers ( p <0.05) were significantly more frequent in CG. As regard to TMD symptoms, arthralgia and tinnitus didn't showed significant differences between the two groups, while neck/shoulders and masticatory muscle pain was significantly more referred in IIM patients than in the CG ( p <0.05). About TMJ signs, sounds were overlapping in the two groups: click=11.1% in both IIM patients and CG ( p >0.05), crepitation in 11.1% of IIM and 9.3% of controls ( p >0.05). No significant difference was detected about deflection (9.3%, p >0.05), while deviation was wider in CG ( p <0.05). Active opening and lateralities showed no significant differences, while endfeel was significantly increased in IIM group for a higher presence of muscular contracture. Bruxism was present only in CG. Conclusion: The data collected from this observational study seem to support the existence of a relationship between the prevalence of TMD symptoms and signs as well as oral features in patients with myositis. A remarkable reduction of salivary flow and dysphagia were more frequent and severe in IIM patients, as well as muscle contracture and myofacial pain evoked by palpation, this result being highly significant., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Temporomandibular disorder (TMD) is an oral dentofacial disease that is related to multiple factors such as disordered dental occlusion, emotional stress, and immune responses. In the past decades, tumor necrosis factor-alpha (TNF-α), a pleiotropic cytokine, has provided valuable insight into the pathogenesis of TMD, particularly in settings associated with inflammation. It is thought that TNF-α participates in the pathogenesis of TMD by triggering immune responses, deteriorating bone and cartilage, and mediating pain in the temporomandibular joint (TMJ). Initially, TNF-α plays the role of "master regulator" in the complex immune network by increasing or decreasing the production of other inflammatory cytokines. Then, the effects of TNF-α on cells, particularly on chondrocytes and synovial fibroblasts, result in pathologic cartilage degradation in TMD. Additionally, multiple downstream cytokines induced by TNF-α and neuropeptides can regulate central sensitization and inflammatory pain in TMD. Previous studies have also found some therapies target TMD by reducing the production of TNF-α or blocking TNF-α-induced pathways. All this evidence highlights the numerous associations between TNF-α and TMD; however, they are currently not fully understood and further investigations are still required for specific mechanisms and treatments targeting specific pathways. Therefore, in this review, we explored general mechanisms of TNF-α, with a focus on molecules in TNF-α-mediated pathways and their potential roles in TMD treatment. In view of the high clinical prevalence rate of TMD and damage to patients' QOL, this review provides adequate evidence for studying links between inflammation and TMD in further research and investigation.

Objective(s): It is well appreciated that traditional analgesic delivery routes used to treat pain associated with temporomandibular disorder (TMD) often have harmful unintended side effects as a consequence of systemic distribution. Further, localized delivery of analgesic medication via intra-articular injections involves a different set of issues limiting their clinical viability. As an option, transdermal analgesic delivery provides for prolonged pain relief and flexibility in dose administration, while limiting systemic exposure and minimizing adverse events. Incorporation of a novel electroporation technique may further increase transdermal drug penetration into synovial tissue/fluid and enhance pain reduction. The present feasibility study compares the effectiveness of an electroporation-enhanced transdermal application of diclofenac sodium to a conventional intra-articular injection of triamcinolone acetonide suspension (corticosteroids) to treat patients with TMD associated pain., Methods: Pre- and post-treatment maximal incisal mouth opening (MIO), pain visual analog scale (VAS) and surface electromyography (EMG) of 22 patients treated with electroporation-enhanced diclofenac and 37 patients treated with corticosteroids injections were collected and analyzed., Results: In general, patients treated with electroporation exhibited better results in terms of pain improvement (corrected p-value = .01) compared to the standard treatment, but both methods were similarly effective for improvement of MIO (corrected p-value = .71) and improvement of all EMG indices (corrected p-values ≥ .05)., Conclusion: The enhancing effect of electroporation in transdermal delivery of diclofenac sodium was demonstrated by decreased pain, increase MIO and EMG improvement to normal values. Its analgesic and inflammatory results are comparable with standard treatment offered by corticosteroids., (© 2020 The Authors. Clinical and Experimental Dental Research published by John Wiley & Sons Ltd.)

The temporomandibular joint (TMJ) is a fibrocartilaginous tissue critical for chewing and speaking. In patients with temporomandibular disorders (TMDs), permanent tissue loss can occur. Recapitulating the complexity of TMDs in animal models is difficult, yet critical for the advent of new therapies. Synovial fluid from diseased human samples revealed elevated levels of tumor necrosis factor alpha (TNF-alpha). Here, we propose to recapitulate these findings in mice by subjecting murine TMJs with TNF-alpha or CFA (Complete Freund's Adjuvant) in mandibular condyle explant cultures and by local delivery in vivo using TMJ intra-articular injections. Both TNF-alpha and CFA delivery to whole mandibular explants and in vivo increased extracellular matrix deposition and increased cartilage thickness, while TNF-alpha treated explants had increased expression of inflammatory cytokines and degradative enzymes. Moreover, the application of TNF-alpha or CFA in both models reduced cell number. CFA delivery in vivo caused soft tissue inflammation, including pannus formation. Our work provides two methods of chemically induced TMJ inflammatory arthritis through a condyle explant model and intra-articular injection model that replicate findings seen in synovial fluid of human patients, which can be used for further studies delineating the mechanisms underlying TMJ pathology., Competing Interests: The authors have declared that no competing interests exists.

Objectives: Magnetic resonance imaging (MRI) is a standardized method for assisting joint diagnosis. To validate the reliability of different imaging-based grading systems, this study examined (1) the associations between grading systems for osseous change, joint effusion, and the Wilkes classification of temporomandibular joint (TMJ) disorders and (2) the correlation between cytokines in synovial fluid and imaging-based joint scores., Materials and Methods: Twenty-seven patients, who routinely received numeric rating scale (NRS) and MRI assessment before TMJ arthrocentesis, were enrolled. Each joint was evaluated through the grading criteria for severity of osseous change and joint effusion by blinded observers using MRI. ImageJ was employed for classifying joint effusion. Joint synovial fluid, collected through arthrocentesis, was examined for cytokine expression by using a Luminex multiplex assay. All data were analyzed using the Pearson correlation analysis., Results: The Wilkes classification was strongly correlated with osseous change scores, but not with joint effusion scores. Joint effusion scores significantly correlated with NRS scores, but not with the Wilkes classification and osseous change scores. Compared with osseous change scores, joint effusion scores had a higher correlation with the levels of inflammatory cytokines (interleukin (IL)-8 and soluble IL-6 receptor (sIL-6R)) and with anti-inflammatory cytokines (soluble tumor necrosis factor receptors I and II (sTNF-RI/II))., Conclusions: In patients with TMJ disorders, MRI grades are strongly correlated with NRS scores and levels of cytokines (IL-8, sIL-6R, and sTNF-RI/II) in the synovial fluid., Clinical Relevance: Joint effusion scoring can be a reliable and valid indicator for pathological assessment of TMJ disorders.

Temporomandibular disorders (TMD) are a common stomatognathic disease affecting all age groups. Patients with internal derangement (ID) or osteoarthritis (OA) of temporomandibular joint (TMJ) often have TMJ synovitis. When TMJ synovial membrane is damaged, many inflammatory cytokines are produced and secreted from TMJ synoviocytes to synovial fluid of TMJ. It has been widely reported that many kinds of biologic factors are produced from TMJ synoviocytes stimulated with interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha. One of the major symptoms of TMD is pain of the TMJ. Many study groups have studied relations between the development of TMJ pain and biologic factors secreted into synovial fluid of TMJ. Here, we summarize previous reports trying to elucidate this correlation. On the other hand, it has been reported that a new molecular mechanism of IL-1beta secretion called inflammasome is involved in several diseases with sterile inflammation. Because TMJ synovitis with ID and OA of TMJ is also sterile inflammation, inflammasome may be involved in the development of TMJ synovial inflammation. This review describes some molecular mechanisms underlying inflammation in TMJ, especially in TMJ synovitis, which may be useful for the development of new therapies against TMD.

Temporomandibular joint (TMJ) is frequently involved with rheumatoid arthritis with a high prevalence that could result in a chronic pain state. Once the disease is established in the joint, the antigen-specific immune reaction initiates a neuro-immune cascade of events that causes sensitization of the central nervous system. This study establishes animal experimental models that evaluate the chronicity of albumin-induced arthritis hypernociception in the TMJ. Antigen-induced arthritis was generated in rats with methylated bovine serum albumin (mBSA) diluted in complete Freund's. Intra-articular injection of mBSA (10 µg/TMJ/week) during 3 weeks resulted in a persistent inflammatory hypernociception which was characterized by an inflammatory episode characterized by the increased of lymphocytes, macrophages and pro-inflammatory interleukins IL-12 and IL-18. The persistent model of inflammatory hypernociception induced by arthritis in the TMJ elicited protein levels of P2X7 receptors, cathepsin S and fractalkine in the trigeminal subnucleus caudalis. Overall, the results of the present work suggest that a persistent inflammatory hypernociception of albumin-induced arthritis in the TMJ leads to the activation of the central nervous system signaling by P2X7/cathepsin S/fractalkine pathway., (Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.)

It is well accepted that the presence of cytokines belonging to the Th1/Th17/Th22 axis of immuno-inflammatory response in the joint environment, such as IL-1β, IL-17 and IL-22, respectively, are associated with pathogenesis of several synovial joint degenerative disorders. During temporomandibular joint osteoarthritis (TMJ-OA), IL-1β and IL-17 have been implicated in the inflammation and resorption of sub-chondral bone; however, the role of Th22 response in the TMJ-OA pathophysiology has not been established. This study aimed to compare the expression of Th1/Th17/Th22-type cytokines, chemokines and chemokine receptors in synovial fluid samples obtained from TMJ-OA or disk displacement with reduction (DDWR) patients. In addition, it aimed to associate these levels with joint pain, imagenological signs of bone degeneration, RANKL production, osteoclastogenesis and osteoclast-induced bone resorption. Higher levels of IL-1β, IL-17 and IL-22 were expressed in TMJ-OA compared with DDWR subjects, and these increased levels significantly correlated with RANKL expression, joint pain and articular bone degeneration. Higher levels of CCR5, CCR6 and CCR7, as well as their respective ligands CCL5 and CCL20, responsible for recruitment of IL-1β, IL-17 and IL-22-producing cells, were over-expressed in TMJ-OA compared with DDWR subjects. Osteoclastogenesis and osteoclast-induced bone resorption were significantly greater in presence of synovial fluid from TMJ-OA compared with DDWR subjects. These data demonstrate that cytokines, CCLs and CCRs associated with the Th1/Th17/Th22 axis of immuno-inflammatory response are involved in TMJ-OA pathogenesis. These findings suggest that IL-22 is involved in the RANKL expression in TMJ-OA, which in turn induces differentiation of osteoclasts and subsequent resorption of sub-chondral bone., (© 2018 John Wiley & Sons Ltd.)

Evidence-based clinical diagnostic criteria for temporomandibular joint (TMJ) arthritis are not available. To establish (i) criteria for clinical diagnosis of TMJ arthritis and (ii) clinical variables useful to determine inflammatory activity in TMJ arthritis using synovial fluid levels of inflammatory mediators as the reference standard. A calibrated examiner assessed TMJ pain, function, noise and occlusal changes in 219 TMJs (141 patients, 15 healthy individuals). TMJ synovial fluid samples were obtained with a push-pull technique using the hydroxycobalamin method and analysed for TNF, TNFsRII, IL-1β, IL-1ra, IL-1sRII, IL-6 and serotonin. If any inflammatory mediator concentration exceeded normal, the TMJ was considered as arthritic. In the patient group, 71% of the joints were arthritic. Of those, 93% were painful. About 66% of the non-arthritic TMJs were painful to some degree. Intensity of TMJ resting pain and TMJ maximum opening pain, number of jaw movements causing TMJ pain and laterotrusive movement to the contralateral side significantly explained presence of arthritis (AUC 0.72, P < .001). Based on these findings, criteria for possible, probable and definite TMJ arthritis were determined. Arthritic TMJs with high inflammatory activity showed higher pain intensity on maximum mouth opening (P < .001) and higher number of painful mandibular movements (P = .004) than TMJs with low inflammatory activity. The combination TMJ pain on maximum mouth opening and Contralateral laterotrusion <8 mm appears to have diagnostic value for TMJ arthritis. Among arthritic TMJs, higher TMJ pain intensity on maximum mouth opening and number of mandibular movements causing TMJ pain indicates higher inflammatory activity., (© 2018 John Wiley & Sons Ltd.)

A rapidly increasing number of mandibular condylar fractures and some complications related to injuries of temporomandibular elements make this study important. Intra-articular disorders lead to secondary pathological findings such as osteoarthritis, deforming osteoarthrosis, and temporomandibular joint ankylosis that limits mouth opening, mastication, swallowing, breathing, and decreased/lost working capacity or disability. Early diagnosis of intra-articular disorders can prevent from long-lasting functional complications caused by temporomandibular joint injuries. This study was performed for the purpose of early detection and investigation of organic pathological changes in the cartilaginous and osseous tissues of the temporomandibular joint caused by traumatic fractures of the mandibular condyle. Twenty patients underwent a general clinical examination, magnetic resonance imaging (MRI), and immune-enzyme testing for biochemical markers of connective tissue injury (pyridinoline and deoxypyridinoline) in urine. Disk dislocation, deformation, adhesion, perforation or squeeze, tension or disruption of ligaments, and injury of articular surfaces are among complications of mandibular fractures that can be revealed on MRI. As regards biochemical findings, we revealed a sharp rise in the levels of pyridinoline and deoxypyridinoline before treatment and a lack of stabilization within 21 days of treatment.

Temporomandibular disorders (TMD) are a set of conditions characterized by pain and dysfunction in the temporomandibular joint and muscles of mastication. These pain conditions are associated with considerable morbidity, societal costs, and reduced quality of life. The prevalence varies between 4% and 10%, with females at higher risk, and a higher prevalence occurs during reproductive years. The increased prevalence of TMD in females and low prevalence in childhood reinforce that sex hormones, like estrogen, play an important, complex role in the pathophysiology of these disorders. The goal of this study was to determine whether women with TMD exhibit a monocytic hyperinflammatory response compared with control women, and to examine associations of monocytic inflammatory responses with clinical pain. Eighteen women, aged 18 to 35 y, were seen during their follicular menstrual phase. A blood sample was collected, a clinical questionnaire about pain history was administered, and a Research Diagnostic Criteria (RDC) exam was performed. Extracted monocytes were stimulated with the toll-like receptor (TLR)-4 ligand, lipopolysaccharide (LPS), in the presence and absence of estrogen, and the levels of IL6 expression evaluated. Women with TMD showed a systemic hyperinflammatory phenotype, manifested by an increased monocytic release of cytokines after an inflammatory insult, and this was further increased by estrogen. In addition, monocytes from participants who self-reported more pain on the VAS scale produced higher levels of IL6 compared with those from participants who self-reported lower pain sensitivity. These data suggest that an estrogen-induced hyperinflammatory phenotype in women with TMD may at least in part contribute to heightened clinical pain, perhaps via central sensitization., Competing Interests: The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article.

The aim of this study was to find out if reactive arthritis was involved in the aetiology of chronic closed lock of the temporomandibular joint (TMJ) by looking for bacterial antigens in the synovial membrane of the TMJ, and by studying the antibody serology and carriage of human leucocyte antigen (HLA) B27 in patients with chronic closed lock. Patients with reciprocal clicking and healthy subjects acted as controls. We studied a total of 43 consecutive patients, 15 with chronic closed lock, 13 with reciprocal clicking, and 15 healthy controls with no internal derangements of the TMJ. Venous blood samples were collected from all subjects for measurement of concentrations of HLA tissue antigen and serology against Chlamydia trachomatis, Yersinia enterocolitica, Salmonella spp., Campylobacter jejuni, and Mycoplasma pneumoniae. Samples of synovial tissue from patients with closed lock and reciprocal clicking were obtained during discectomy and divided into two pieces, the first of which was tested by strand displacement amplification for the presence of C trachomatis, and the second of which was analysed for the presence of species-specific bacterial DNA using 16s rRNA pan-polymerase chain reaction (PCR). There were no significant differences between the groups in the incidence of antibodies against M pneumoniae, Salmonella spp. or Y enterocolitica. No patient had antibodies towards C trachomatis or C jejuni. We found no bacterial DNA in the synovial fluid from any patient. The HLA B27 antigen was present in 2/15 subjects in both the closed lock and control groups, and none in the reciprocal clicking group. In conclusion, reactive arthritis does not seem to be the mechanism of internal derangement of the TMJ., (Copyright © 2015. Published by Elsevier Ltd.)

The aim was to investigate how endogenous cytokine control of tumor necrosis factor (TNF) influences temporomandibular joint (TMJ) pain in relation to the role of anti-citrullinated peptide antibodies (ACPA) in patients with rheumatoid arthritis (RA). Twenty-six consecutive patients with TMJ RA were included. Temporomandibular joint pain intensity was assessed at rest, on maximum mouth opening, on chewing, and on palpation. Mandibular movement capacity and degree of anterior open bite (a clinical sign of structural destruction of TMJ tissues) were also assessed. Systemic inflammatory activity was assessed using the Disease Activity Score in 28 joints (DAS28) for rheumatoid arthritis. Samples of TMJ synovial fluid and blood were obtained and analyzed for TNF, its soluble receptor, soluble TNF receptor II (TNFsRII), and ACPA. A high concentration of TNF in relation to the concentration of TNFsRII in TMJ synovial fluid was associated with TMJ pain on posterior palpation on maximum mouth opening. The ACPA concentration correlated significantly to the TNF concentration, but not to the TNFsRII concentration, indicating that increased inflammatory activity is mainly caused by an insufficient increase in anti-inflammatory mediators. This study indicates that TMJ pain on palpation in patients with RA is related to a deficiency in local cytokine control that contributes to increased inflammatory activity, including sensitization to mechanical stimuli over the TMJ., (© 2015 Eur J Oral Sci.)

Objective: To investigate if TNF, IL-1 or their endogenous controls, in relation to ACPA, are associated with radiological signs of ongoing temporomandibular joint (TMJ) bone tissue resorption and disc displacement in RA patients., Methods: Twenty-two consecutive outpatients with TMJ of RA were included. Systemic inflammatory activity was assessed by DAS28. The number of painful regions in the body and ESR, CRP, RF and ACPA were analyzed. TMJ synovial fluid and blood samples were obtained and analyzed for TNF, TNFsRII, IL-1ra, IL-1sRII and ACPA. The ratios between the mediators and their endogenous control receptors were used in the statistical analysis. Magnetic resonance imaging was performed in closed- and open-mouth positions and evaluated regarding disc position and presence of condylar and temporal erosions of the TMJ., Results: A high TNF level in relation to TNFsRII in TMJ synovial fluid correlated to the degree of TMJ condylar erosion. A high IL-1ra level in relation to TNF in TMJ synovial fluid was also correlated to the degree of TMJ condylar erosion. The total degree of TMJ condylar erosion was correlated with the number of painful regions., Conclusion: This study indicates that TNF in TMJ synovial fluid mediates TMJ cartilage and bone tissue resorption in RA. The study also suggests that the degree of endogenous cytokine control is of importance for development of bone tissue destruction.

The aim of this study was to evaluate the peripheral effect of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) in albumin-induced arthritis in temporomandibular joint (TMJ) of rats. Antigen-induced arthritis (AIA) was generated in rats with methylated bovine serum albumin (mBSA) diluted in complete Freund׳s adjuvant. Pretreatment with an intra-articular injection of 15d-PGJ2 (100 ng/TMJ) before mBSA intra-articular injection (10 µg/TMJ) (challenge) in immunized rats significantly reduced the albumin-induced arthritis inflammation. The results demonstrated that 15d-PGJ2 was able to inhibit plasma extravasation, leukocyte migration and the release of inflammatory cytokines IL-6, IL-12, IL-18 and the chemokine CINC-1 in the TMJ tissues. In addition, 15d-PGJ2 was able to increase the expression of the anti-adhesive molecule CD55 and the anti-inflammatory cytokine IL-10. Taken together, it is possible to suggest that 15d-PGJ2 inhibit leukocyte infiltration and subsequently inflammatory process, through a shift in the balance of the pro- and anti-adhesive properties. Thus, 15d-PGJ2 might be used as a potential anti-inflammatory drug to treat arthritis-induced inflammation of the temporomandibular joint., (Copyright © 2014. Published by Elsevier B.V.)

Objectives: β-defensin-4 is a member of antimicrobial peptides (APs) of the immunity system. This molecule has antimicrobial activity but it seems to be involved in articular inflammatory processes too, as it happens during osteoarthritic disease (OA). Considering the possible relation existing between (OA) and temporomandibular disorders (TMD), the aim of our study was to evaluate immunohistochemically the presence of β- defensin-4 in pathological temporomandibular joint (TMJ) discs affected by internal derangement without reduction (ADDwoR)., Design: Eighteen TMJ-displaced disc specimens were considered in this study and were analysed by immunohistochemical evaluation. They were compared with a control sample of sixteen healthy discs and two scores, intensity of staining (IS) and extent score (ES) were estimated., Results: Findings of our analysis showed a significant difference between control and study sample (P < 0.001). IS and ES of control sample and pathological sample were 1 and 4 respectively., Conclusion: Our results confirmed the presence of β-defensin-4 in human TMJ discs affected by ADDwoR, hypothesing a possible role of this molecule in articular bone disruption., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)

Aim: A study was performed on the articular disk and periarticular tissues of the temporo-mandibular joint (TMJ) with immunohistochemical techniques to give evidence to the presence of neuroreceptors (NRec) in these sites., Methods: The study was carried out on tissue samples obtained from 10 subjects without TMJ disease and from 7 patients with severe TMJ arthritis and arthrosis. We use antibodies directed against following antigens: Gliofibrillary Acidic Protein (GFAP), Leu-7, Myelin Basic Protein (MBP), Neurofilaments 68 kD (NF), Neuron Specific Enolase (NSE), S-100 protein (S-100) and Synaptophysin (SYN)., Results: This study revealed that Ruffini's-like, Pacini's-like and Golgi's-like receptors can be demonstrated in TMJ periarticular tissues and that free nervous endings are present in the subsynovial tissues but not within the articular disk. We observed elongated cytoplamic processes of chondrocytes that demonstrated strong S-100 immunoreactivity but they were unreactive with all other antibodies. These cytoplamic processes were more abundant and thicker in the samples obtained from patients with disease TMJ., Conclusion: The results of this study confirm that different Nrec are detectable in TMJ periarticular tissues but they are absent within the articular disk. In the latter site, only condrocytic processes are evident, especially in diseased TMJ, and they might have been confused with nervous endings in previous morphological studies. Nevertheless the absence of immunoreactivity for NF, NSE and SYN proves that they are not of neural origin.

To determine whether the vestibular nuclei are affected by inflammation of temporomandibular joint (TMJ) region, we studied vestibular nucleus neural activity using two experimental groups: (1) normal saline 0.1cm(3) injection at right TMJ region, (2) 10% formalin 0.1cm(3) injection at right TMJ region. Neural activity after 24 hours was assessed by immunohistochemical staining with free-floating section at the level of interaural -1.30 mm to -2.00 mm for c-Fos. In inflammation group, formalin injection produced a bilateral increase in c-Fos at vestibular nucleus with ipsilesional side higher activity. In control group, expression of c-Fos protein was also observed in the vestibular nucleus (VN), especially MVN. But stain intensity of Fos-positive neurons was much weaker and mean number of c-Fos positive cells was fewer than inflammation group. This result suggests that there is a close neural connection between TMJ and vestibular nucleus, especially in case of inflammation., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

This study was undertaken to examine the alteration of masseter and plasma interleukin-6 after inducing occlusal interference and chronic stress. Male Wistar rats were submitted to chronic stress procedure, exposed to occlusal interference, or exposed to both mentioned procedures. Whole blood and masseter tissue were collected to determine interleukin-6 level, measured by means of ELISA. Masseter pain was evaluated using the orofacial formalin test. Masseter interleukin-6 level was significantly higher in animals submitted to combination of occlusal interference and chronic stress than in the control group (p<0.05). There was positive and significant correlation between pain response and masseter interleukin-6 level (r=0.5741; p<0.0003). No significant differences in plasma interleukin-6 level were found between groups (p>0.05), as well as no correlation with pain (p>0.05). Combination of occlusal interference and chronic stress leads to strong local reaction characterized by high levels of masseter interleukine-6. High concentrations of muscle interleukin-6 and its correlation with pain point to inflammatory background of masticatory muscle pain.

For reasons unknown, temporomandibular disorder (TMD) can manifest as localized pain or in conjunction with widespread pain. We evaluated relationships between cytokines and TMD without or with widespread palpation tenderness (TMD-WPT or TMD+WPT, respectively) at protein, transcription factory activity, and gene levels. Additionally, we evaluated the relationship between cytokines and intermediate phenotypes characteristic of TMD and WPT. In a case-control study of 344 females, blood samples were analyzed for levels of 22 cytokines and activity of 48 transcription factors. Intermediate phenotypes were measured by quantitative sensory testing and questionnaires asking about pain, health, and psychological status. Single nucleotide polymorphisms (SNPs) coding cytokines and transcription factors were genotyped. TMD-WPT cases had elevated protein levels of proinflammatory cytokine monocyte chemotactic protein (MCP-1) and antiinflammatory cytokine interleukin (IL)-1ra, whereas TMD+WPT cases had elevated levels of proinflammatory cytokine IL-8. MCP-1, IL-1ra, and IL-8 were differentially associated with experimental pain, self-rated pain, self-rated health, and psychological phenotypes. TMD-WPT and TMD+WPT cases had inhibited transcription activity of the antiinflammatory cytokine transforming growth factor β1 (TGFβ1). Interactions were observed between TGFβ1 and IL-8 SNPs: an additional copy of the TGFβ1 rs2241719 minor T allele was associated with twice the odds of TMD+WPT among individuals homozygous for the IL-8 rs4073 major A allele, and half the odds of TMD+WPT among individuals heterozygous for rs4073. These results demonstrate how pro- and antiinflammatory cytokines contribute to the pathophysiology of TMD and WPT in genetically susceptible people. Furthermore, they identify MCP-1, IL-1ra, IL-8, and TGFβ1 as potential diagnostic markers and therapeutic targets for pain in patients with TMD., (Published by Elsevier B.V.)

Background: In juvenile idiopathic arthritis involvement of the temporomandibular joints (TMJs) is often associated with mandibular growth deviations. The relation between the growth deviations and severity of the inflammation, condylar shape, the micro-architecture, and the quality of the bone has not previously been investigated. This paper studies the effect on the bony structures in mandibular condylar development in rabbits with antigen-induced arthritis., Methods: Included were 42 juvenile rabbits with ovalbumin-induced arthritis of the TMJs treated with intraarticular saline, intraarticular etanercept or subcutaneous etanercept. A TMJ from each animal was scanned using micro-computed tomography and structural parameters were calculated. Three-dimensional reconstructions of the mandibular condyle were scored blindly as normal or abnormal. TMJs were stratified for condylar morphology and were evaluated against data on trabecular structural parameters, inflammation, degree of mineralization, overall mandibular growth, and mineral apposition rate., Results: Abnormal morphology were seen in 15/32 animals available for data analysis. Erosions were an uncommon finding. Abnormal morphology was strongly related to the degree of inflammation. The trabecular separation was larger in group with abnormal morphology than in the group with normal morphology. Abnormal condylar morphology was not associated with overall mandibular growth. No differences were observed in mineral apposition rate. No differences in structural parameters were seen according to treatment modality., Conclusion: We showed that severe inflammation in the TMJs during mandibular development was associated with morphological changes in the mandibular condyle. These changes were predominantly seen at the macro-morphological level and only very few differences were structural., (© 2010 John Wiley & Sons A/S.)

The aim of this study was to determine the presence of HLA alleles, specifically HLA-DR alleles, and to correlate them with clinical and radiological features of patients with degenerative processes (DP) of the temporomandibular joint (TMJ). The final goal was to determine which allele can be used to identify patients having more aggressive forms of the articular pathologies. Thirty-two (32) Caucasian patients with DP of the TMJ were included in the study. The SSOP (Luminex Corp., Austin, TX) method was used to determine class II HLA alleles. The presence of HLA-II DR in patients with DP of the TMJ was 98%. The presence of HLA was significantly higher in patients with DP of the TMJ than in healthy subjects (66%) (p=0.003). HLA DR52 was significantly more frequent in patients than in healthy individuals (40.62% vs. 13.79%, p = 0.041). While the percentage of DR11 positive individuals was also higher among patients than among healthy control subjects, the association with DP of the TMJ was not significant (p=0.220). Patients having the DR52 allele had higher deformation or DP. It was concluded that HLA-DR54 and DR11 alleles are associated with a higher susceptibility to DP of the TMJ, and HLA-DR54 and DR52 are associated with a higher severity of DP.

Aims: To establish a new model of zymosan-induced temporomandibular joint (TMJ) arthritis in the rat and to investigate the role of nitric oxide., Methods: Inflammation was induced by an intra-articular injection of zymosan into the left TMJ. Mechanical hypernociception, cell influx, vascular permeability, myeloperoxidase activity, nitrite levels, and histological changes were measured in TMJ lavages or tissues at selected time points. These parameters were also evaluated after treatment with the nitric oxide synthase (NOS) inhibitors L-NAME or 1400 W., Results: Zymosan-induced TMJ arthritis caused a time-dependent leucocyte migration, plasma extravasation, mechanical hypernociception, and neutrophil accumulation between 4 and 24 h. TMJ immunohistochemical analyses showed increased inducible NOS expression. Treatment with L-NAME or 1400 W inhibited these parameters., Conclusion: Zymosan-induced TMJ arthritis is a reproducible model that may be used to assess both the mechanisms underlying TMJ inflammation and the potential tools for therapies. Nitric oxide may participate in the inflammatory temporomandibular dysfunction mechanisms.

Despite of many years of research, the data regarding interactions between the peripheral nervous system and the immune system remain incomplete. Most discoveries concern nociceptive signaling pathways. Among pain conditions with the utmost social implications, a large percentage exhibits the inflammatory process as an underlying cause. Here the most prominent are several disorders associated with the trigeminal nerve, including migraine, trigeminal neuralgia, and temporomandibular disorders. The molecular mechanisms of the trigeminal nociceptive transmission in general, and chronic trigeminal pain in particular, are almost completely unknown. Recent studies have shown that cytokines IL-1beta, IL-6 and TNF-alpha play a very important role in the pathogenesis of the immune response within the peripheral endings of trigeminal ganglion neurons. It has also been demonstrated that some proinflammatory cytokines (e.g., IL-1beta, TNF-alpha) are capable of sensitizing nociceptive neurons. Modulation of inflammatory response can thus influence pain reaction.

Synovitis, which is characterized by the infiltration of inflammatory cells, often accompanies progression of temporomandibular joint disorder (TMD) symptoms. Because IL-1β is elevated in synovial fluids obtained from TMDs, we hypothesized that IL-1β-responsive genes in synoviocytes may help identify the putative genes associated with synovitis. Using microarray analysis, we found that monocyte chemoattractant protein-1 (MCP-1) mRNA levels were elevated in IL-1β-stimulated synoviocytes. MCP-1 is a member of the chemokine superfamily. The production of MCP-1 was increased in synoviocytes treated with IL-1β. When IL-1β was injected into the cavities of rat TMJs, inflammatory cells and MCP-1-positive cells were detected in the synovial tissues. Furthermore, MCP-1 levels were higher in synovial fluids from individuals with pain compared with those without pain. Inhibitors of MAP-kinases and NF-κB reduced IL-1β-induced MCP-1 production. These results suggest that MCP-1 stimulated by IL-1β is one of the factors associated with the inflammatory progression of TMDs.

Purpose: The purpose of this study is to clarify the significance of joint effusion (JE) on T2-weighted magnetic resonance images of the temporomandibular joint (TMJ) in comparison to various soluble cytokine receptors in the synovial fluid of patients with temporomandibular disorders (TMDs)., Patients and Methods: Magnetic resonance imaging of 55 TMJs of 55 patients with TMD was performed, and synovial fluid samples were obtained on the same day. The grade of JE was evaluated on a scale from 0 to 3, with grade 0 indicating the absence of JE and grades 1 to 3 indicating the presence of JE. Correlations were measured between JE and the concentrations of soluble tumor necrosis factor receptors I and II, interleukin (IL) 6 soluble receptor, IL-1 soluble receptor type II, and IL-1 receptor antagonist and protein in the synovial fluid samples., Results: The mean concentrations of cytokine receptors in the synovial fluid were significantly higher in the 30 joints with JE than in the 25 joints without JE. There were no correlations between the JE grade and the level of any mediators., Conclusion: Increased levels of cytokine receptors are likely to influence the expression of JE and may play important roles in the pathogenesis of TMD. These results also suggest that JE may reflect synovial inflammation of the TMJ., (Copyright 2010 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to elucidate the relationship of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) to temporomandibular disorder with clinical symptoms such as pain, joint sounds, and mouth opening limitation by analysis of the level of these molecules in the synovial fluid., Patients and Methods: Twenty-four patients with chief complaints of pain, mouth opening limitation, and clicking sounds were selected as the experimental group and compared with 5 healthy subjects. After joint lavage with arthrocentesis, diluted synovial fluid was collected and enzyme-linked immunosorbent assay was done for analysis of TNF-alpha and IL-6 in 24 experimental patients and 5 healthy subjects., Results: The synovial levels of TNF-alpha and IL-6 were elevated in the experimental group compared with the healthy control group, but no significant correlation was established. The synovial levels of TNF-alpha and IL-6 were elevated in the acute pain group compared with the chronic pain group, but no significant correlation was established., Conclusion: In our analysis of 2 proinflammatory cytokines, TNF-alpha and IL-6, in the synovial fluid of temporomandibular disorder patients with symptoms of pain, mouth opening limitation, and clicking, both were elevated without statistical significance., (Copyright 2010 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

The pathophysiology of temporomandibular joint pain is not well understood. A significant amount of research has been conducted to evaluate synovial fluid in these patients and in healthy controls. Qualitative and quantitative analyses of the synovial fluid have shown a significant difference between these groups. A multitude of inflammatory mediators and degradation products have been identified. The concentration of these products has been shown to correlate with several clinical parameters including pain, chronicity, severity of degenerative change, and response to treatment. A common inflammatory pathway would appear to be involved in most patients. At the present time, synovial fluid analysis does not have the sensitivity or specificity to allow specific diagnoses and targeted treatment. Continued research with the specific aim of establishing more appropriate therapeutic modalities based on the biochemical pathways is warranted.

Background: In this study, we analyzed the gene expression profile of fibroblast-like synoviocyte (FLS) cultures from the temporomandibular joint (TMJ) to identify candidate genes associated with intracapsular pathologic conditions of TMJ. Cyclooxygenase (COX)-2 was one of the genes in FLS upregulated following stimulation by interleukin (IL)-1beta, a cytokine thought to play a key role in several pathological conditions. This study investigated the expression of COX-1 and COX-2 in cultured human FLS and rat TMJ synovium following stimulation with IL-1beta., Methods: RNA was isolated from human FLS after IL-1beta treatment. COX-1 and -2 expression was examined using a GeneChip and real-time polymerase chain reaction. Prostaglandin E(2) (PGE(2)) levels in conditioned media from FLS were measured using enzyme-linked immunosorbent assay. Synovial tissues from TMJs of IL-1beta-injected rats were examined for COX-1 and COX-2 expression by immunohistochemical staining., Results: Following treatment of FLS with IL-1beta, expression of the COX-2 gene increased up to 8 h and peaked at 4 h, whereas COX-1 expression did not change. Stimulation with IL-1beta increased the level of PGE(2) in conditioned media of cultured FLS in a time-dependent manner up to 48 h. Immunohistochemistry showed a strong positive staining for COX-2 in the lining and sub-lining synovial tissues of the TMJ of IL-1beta-injected rats. In contrast, staining for COX-1 was the same in synovial tissues with and without IL-1beta injection., Conclusion: These data suggest that COX-2 expression stimulated by IL-1beta stimulates the production of PGE(2) in FLS and plays important roles in the progression of inflammation in TMJ.

Objective: The aim of this study was to evaluate the levels of interleukin (IL)-1beta, IL-6, IL-8, IL-11, and tumor necrosis factor (TNF)-alpha in temporomandibular joint (TMJ) synovial fluid of the patients with internal derangement before and 2 weeks after arthrocentesis., Study Design: Forty TMJs of 35 patients (29 females and 6 males, mean age 22.9 years) were included to the study. TMJs were divided into 2 groups: disc displacement with reduction (Group 1, n = 24) and disc displacement without reduction (Group 2, n = 16). Synovial fluid samples were obtained before and 2 weeks after arthrocentesis. IL-1beta, IL-6, IL-8, IL-11, and TNF-alpha concentrations were measured by using specific kits., Results: Two weeks after the arthrocentesis procedures, all cytokines were found to be significantly decreased (P < .05) both in Group 1 and Group 2. The difference between 2 groups was insignificant (P > .05)., Conclusion: Arthrocentesis is an effective technique for eliminating the studied cytokines from the TMJ synovial fluid.

Purpose: Previous studies made only qualitative assessments of immune cell responses to temporomandibular joint (TMJ) implant wear debris. The aim of this study was to perform a quantitative comparison of inflammatory cell types in TMJ tissues with implant wear debris, TMJ tissues with a history of disc pathology without implant debris, and TMJ tissues from normal control subjects., Materials and Methods: TMJ tissues were collected from the following 3 groups of subjects: 1) individuals with failed TMJ implants (implant group, n = 10), 2) patients with TMJ disc pathology but no history of implant placement (nonimplant surgery group, n = 10), and normal cadaveric tissues with no history of surgery (control group, n = 10). Tissue sections (5 microm) from all subjects were stained with hematoxylin-eosin, after which cell counts were done for 2 types of inflammatory cells: multinucleated giant cells and lymphocytes. Mean inflammatory cell counts from the 3 groups were compared by use of a 1-way analysis of variance procedure and Bonferroni adjustment to maintain an overall type I error rate of .05., Results: Implant group tissues contained significantly more inflammatory cells than tissues from the nonimplant surgery and control groups (P < .0001). Multinucleated giant cells were only present in implant group tissues. Although the high number of multinucleated giant cells present in the implant group obscured a total count of lymphocytes for that group, lymphocyte cell counts were still significantly greater (P < .005) in implant group tissues than in tissues from the other 2 groups., Conclusions: Our data provide quantitative confirmation that the presence of Proplast-Teflon implant (Vitek, Houston, TX) wear debris is associated with a significant increase in the number of local multinucleated giant cells and lymphocytes.

To evaluate the involvement of paratrigeminal nucleus (Pa5) nociceptive neurons in temporomandibular joint (TMJ) inflammation-induced pain and its autonomic correlates, we conducted behavioral, single unit recording and Fos immunohistochemical studies in anesthetized rats. Nocifensive behaviors to mechanical, heat or cold stimulation of the lateral face over the TMJ region were significantly enhanced in the TMJ-inflamed rats for 10-14 days after injection of complete Freund's adjuvant (CFA) into the TMJ and gradually decreased at the end of the 14-day observation period. Lowering of the nocifensive threshold in TMJ-inflamed rats lasted longer in vagus nerve-transected rats than vagus nerve-intact rats. A large number of Fos-like immunoreactive (LI) cells were observed in the Pa5, and half of them were retrogradely labeled with Fluorogold (FG) injected into the parabrachial nucleus. Background activity of Pa5 wide dynamic range and nociceptive specific neurons was significantly higher in the TMJ-inflamed rats when compared with controls. Responses to mechanical stimuli were significantly higher in NS neurons in the TMJ-inflamed rats. All thermal responsive Pa5 neurons were exclusively sensitive to cold and the response to cold was significantly higher in the TMJ-inflamed rats compared with control rats. Vagus nerve stimulation significantly decreased responses to mechanical and cold stimuli as well as the background activity in TMJ-treated rats but not in TMJ-untreated rats. The present findings suggest that populations of Pa5 neurons are nociceptive and involved in TMJ inflammation-induced pain as well as in autonomic processes related to TMJ pain.

Objective: To determine whether there is an association between temporomandibular joint (TMJ) osteoarthritis/osteoarthrosis (OA) and immune system factors in a Japanese sample., Materials and Methods: The records of 41 subjects (7 men, aged 22.0 +/- 3.8 years; 34 women, aged 24.8 +/- 6.3 years) and 41 pair-matched controls (7 men, aged 22.1 +/- 2.3 years; 34 women, aged 24.8 +/- 6.4 years) based on age and gender were reviewed. Information on medical history included local or systemic diseases, details on medication type and use, and the presence of allergies and asthma. Dental history questions referred to details regarding past oral injuries. The validity of the hypothesis, defining allergies and asthma as risk factors in OA, was tested by using a logistic regression analysis., Results: The incidence of allergy was significantly higher in the TMJ OA (P = .008), with a mean odds ratio of 4.125 and a 95% confidence interval of 1.446-11.769., Conclusion: These results suggest that allergy may be a risk factor in association with TMJ OA in this Japanese sample.

Background: To compare the inflammatory changes of antigen-induced temporomandibular joint (TMJ) arthritis in rabbits by different histological methods and to evaluate the immunomodulatory effect of intra-articular corticosteroid injections histologically., Methods: 35 rabbits (10 weeks old) pre-sensibilized with ovalbumin were divided into three groups: a placebo group of five (saline), an arthritis group of 15 (ovalbumin) and a steroid-treated group of 15 (ovalbumin + corticosteroid). Additionally, a group of seven rabbits receiving no sensibilization with ovalbumin and no intra-articular injections served as controls. Histomorphometry of the inflammatory changes in the subsynovial connective tissue (SSCT) of the TMJ included: (i) semi-quantitative (S-Q) scoring of inflammation and synovial proliferation, (ii) thickness measurements and fractional surface and (iii) stereological quantitative assessment of volume and plasma cells in thick sections of the SSCT by an optical fractionator., Results: The histomorphometry showed synovial proliferation in both the arthritis and the steroid groups. The plasma cell count obtained by the optical fractionator was significantly reduced when treating the TMJ with corticosteroids. However, the thickness of the synovial lining and volume of the SSCT as well as S-Q scoring of inflammation showed no difference between the arthritis and the steroid-treated groups. The optical fractionator proved a superior tool compared to S-Q assessments., Conclusion: Counting of plasma cells in the SSCT showed that corticosteroids reduced the inflammation, but did not eliminate it. Semiquantitative scoring of synovial proliferation and inflammation demonstrated low sensitivity regarding changes in immunomodulation in antigen-induced arthritis compared to stereological quantitative estimations using an optical fractionator.

Leukotriene B4 (LTB4) mediates different inflammatory events such as neutrophil migration and pain. The present study addressed the mechanisms of LTB4-mediated joint inflammation-induced hypernociception. It was observed that zymosan-induced articular hypernociception and neutrophil migration were reduced dose-dependently by the pretreatment with MK886 (1-9 mg/kg; LT synthesis inhibitor) as well as in 5-lypoxygenase-deficient mice (5LO(-/-)) or by the selective antagonist of the LTB(4) receptor (CP105696; 3 mg/kg). Histological analysis showed reduced zymosan-induced articular inflammatory damage in 5LO(-/-) mice. The hypernociceptive role of LTB4 was confirmed further by the demonstration that joint injection of LTB4 induces a dose (8.3, 25, and 75 ng)-dependent articular hypernociception. Furthermore, zymosan induced an increase in joint LTB4 production. Investigating the mechanism underlying LTB4 mediation of zymosan-induced hypernociception, LTB4-induced hypernociception was reduced by indomethacin (5 mg/kg), MK886 (3 mg/kg), celecoxib (10 mg/kg), antineutrophil antibody (100 mug, two doses), and fucoidan (20 mg/kg) treatments as well as in 5LO(-/-) mice. The production of LTB4 induced by zymosan in the joint was reduced by the pretreatment with fucoidan or antineutrophil antibody as well as the production of PGE2 induced by LTB4. Therefore, besides reinforcing the role of endogenous LTB4 as an important mediator of inflamed joint hypernociception, these results also suggested that the mechanism of LTB4-induced articular hypernociception depends on prostanoid and neutrophil recruitment. Furthermore, the results also demonstrated clearly that LTB4-induced hypernociception depends on the additional release of endogenous LTs. Concluding, targeting LTB4 synthesis/action might constitute useful therapeutic approaches to inhibit articular inflammatory hypernociception.

Multiple dental diseases are characterized by chronic inflammation, due to the production of cytokines, chemokines, and prostanoids by immune and non-immune cells. Membrane-bound receptors provide a link between the extracellular environment and the initiation of intracellular signaling events that activate common signaling components, including p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor (NF)-kappaB. Although ERK pathways regulate cell survival and are responsive to extracellular mitogens, p38 MAPK, JNK, and NF-kappaB are involved in environmental stress responses, including inflammatory stimuli. Over the past decade, significant advances have been made relative to our understanding of the fundamental intracellular signaling mechanisms that govern inflammatory cytokine expression. The p38 MAPK pathway has been shown to play a pivotal role in inflammatory cytokine and chemokine gene regulation at both the transcriptional and the post-transcriptional levels. In this review, we present evidence for the significance of p38 MAPK signaling in diverse dental diseases, including chronic pain, desquamative disorders, and periodontal diseases. Additional information is presented on the molecular mechanisms whereby p38 signaling controls post-transcriptional gene expression in inflammatory states.

Objective: The objective of this study was to determine if temporomandibular joint (TMJ) samples positive for Chlamydia trachomatis have a greater presence of tumor necrosis factor-alpha (TNFalpha) or interleukin-6 (IL-6) when compared with Chlamydia-negative samples., Study Design: Posterior bilaminar tissue samples removed during TMJ surgery from 70 patients were evaluated. Cryosections were stained using monoclonal antibody that identifies C. trachomatis. The presence of IL-6 and TNFalpha were evaluated by immunostaining in 15 samples positive and in 25 samples negative for the presence of C. trachomatis., Results: Of the 70 TMJ samples, 32 (46%) were positive for C. trachomatis. In 15 samples positive for C. trachomatis, 10 (67%) were positive for TNFalpha and 7 (47%) for IL-6. In 25 samples negative for C. trachomatis, only 4 (16%) were positive for TNFalpha and only 2 (8%) for IL-6. Differences in C. trachomatis-positive samples versus negative were significant for both TNFalpha (P < .002) and IL-6 (P < .008)., Conclusion: The presence of C. trachomatis in the TMJ is associated with a significantly increased presence of TNFalpha and IL-6.

Objectives: The objectives of this study were to assay interleukin 8 (IL-8) in synovial tissues of the temporomandibular joint (TMJ) with symptomatic internal derangement, and to assess its relationship with clinical variables., Study Design: Forty-six joints in 44 patients were examined using an immunohistochemical technique. As controls, 8 joints in 7 subjects with habitual dislocation without pain were also examined., Results: IL-8 was expressed mainly in the blood vessels beneath the lining cells in 37 of the 46 joints (80%) with internal derangement and in 2 of the 8 control joints. The percentage of IL-8-positive cells was significantly higher in the internal derangement group than in the control group (P = .004). The percentage of IL-8-positive cells showed no correlation with joint pain or number of infiltrating cells., Conclusions: IL-8 was up-regulated in inflamed synovial tissues in patients with internal derangement. Because IL-8 has no significant correlation with clinical variables, IL-8 may play a secondary role in the pathogenesis of the internal derangement of the TMJ.

The present study was designed to test the hypothesis that estrogen exacerbates inflammation of the temporomandibular joint (TMJ). Evans blue dye was used to quantify plasma extravasation (PE) around the rat TMJ. In an initial set of experiments, TMJ PE was compared in naïve intact male and female rats, as well as in both groups after complete Freund's adjuvant (CFA)-induced inflammation of the TMJ. In contrast to our hypothesis, TMJ PE was significantly greater in both naïve and CFA-inflamed male rats than in females. To determine whether these differences were due to gonadal hormones, four additional groups of rats were studied: gonadectomized (Gx) males and females, Gx males with chronic testosterone (T) replacement, and Gx females with chronic estrogen (E) replacement. The sex difference in baseline TMJ PE appeared to reflect the actions of T. However, in the presence of TMJ inflammation, T augmented TMJ PE in males, while E attenuated TMJ PE in females. Changes in PE were also assessed in the contralateral TMJ. Results from this analysis indicated that there is a transient contralateral increase in TMJ PE in females but not males. Given that there is an inverse relationship between PE and joint damage, our results suggest that testosterone may mitigate, but estrogen may exacerbate, TMJ damage, particularly in the presence of overt inflammation. Importantly, our results may help explain both the higher prevalence and severity of temporomandibular disorder pain in females than males.

Objective: To investigate the occurrence of selected markers for inflammatory cells and cytokines in patients with chronic polyarthritis (CPA) and temporomandibular joint (TMJ) involvement., Material and Methods: Eleven patients (11 joints) with CPA and TMJ disorder were included in the study. Synovial specimens were obtained during TMJ open surgery and these were subjected to immunohistochemistry on frozen sections post-fixed with paraformaldehyde and with the cell membranes permeabilized by saponin. In all patients, the cytokines IL-1alpha, IL-1beta, IL-1ra, TNFalpha, IFNgamma, IL2, and TGFbeta were investigated using specific antibodies. The occurrence of macrophages and T-lymphocytes was investigated using immunohistochemistry with monoclonal antibodies against antigens CD68 and CD45RO, respectively. In addition, PCNA was used as a marker for cell proliferation., Results: Staining of IL-1alpha, IL-1, and TGF was seen in all 11 specimens, IFN? in 1, TNFalpha in 4, and IL-2 in none. CD45RO-positive T cells were detected in 7 specimens, CD68-positive macrophages in 6, and cell proliferation seen with PCNA was noted in 8., Conclusions: The predominant cytokines of TMJ CPA were IL-1alpha, IL-1beta, and TGFbeta, and there appeared to be no differences between the subgroups (rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) involved. Moreover, the cytokine pattern of TMJ CPA patients seemed to differ from patients with osteoarthritis, as shown in our previous study. The main difference was the absence of IFNgamma and TNFalpha in TMJ CPA patients and a stronger TGFbeta and IL-1alpha expression.

It has been suggested that dental abnormalities lead to temporomandibular joint inflammation and pain that may be mitigated by regular dental care. There is considerable literature on the pathophysiology of equine joint disease including studies on cytokine profiles in diseased appendicular joints. This study examined the effects of age and dental malocclusions summarized as a dental pathology score on equine temporomandibular joint cytokine (IL-1, IL-6, IL-8, TNF alpha and TGF-beta1, -beta2, -beta3) concentrations. TGF-beta3 was not detected in any joint sample. IL-1, IL-6 and TNF alpha were not influenced by age. Foals had significantly lower concentrations of lL-8 and TGF-beta1, and higher levels of TGF-beta2 compared with older horses. Age did not effect cytokine concentration in older horses although there was a trend towards increasing 1L-8 with age. The dental pathology score increased with age in mature horses, however there was no effect of dental pathology score on cytokine concentration. There was no effect of incisor eruption, and presence or number of periodontal lesions on temporomandibular joint cytokine concentration. Our findings indicate that age but not dental pathology affected temporomandibular joint proinflammatory cytokine concentration in this population of horses.

Background: Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labeling (TUNEL) staining is a widely accepted method for the detection of DNA fragmentation in nuclei of apoptotic cells. Tumor necrosis factor (TNF)-alpha is closely associated with changes in condylar cartilage and modulates apoptosis in various tissues including cartilage. The aim of this study was to investigate the relationship between apoptotic chondrocytes and TNF-alpha in a rabbit model of arthritis., Method: Unilateral temporomandibular joint (TMJ) arthritis was induced in 20 adult New Zealand White rabbits. From 1 day to 6 weeks after the induction of arthritis, immunohistochemical analysis for TNF-alpha and TUNEL was performed., Results: In condylar cartilage, TNF-alpha-positive cells and TUNEL-positive cells were localized together. TNF-alpha-positive chondrocytes seemed to precede TUNEL-positive cells., Conclusions: The results of the present study suggest that TNF-alpha may be involved in apoptosis and/or apoptotic necrosis of chondrocytes as TMJ arthritis progresses from the acute to chronic stage.

Introduction: The ankylosing spondylitis is a chronic inflammatory rheumatoid disease with predilection in the axial structures. The temporomandibular joint (TMJ) is involved in 10 to 24% of cases. Ankylosis of the TMJ is exceptional, only 11 cases being reported to date., Observation: A 48-year-old patient had been followed since 1987 for severe ankylosing spondylitis. The patient, known to be positive for tissue antigen HLA B27, was admitted for limitation of mouth opening. At physical examination, mouth opening was reduced to 1cm with no mandibular movements and a stiffness of the cervical spine in flexion. Computed tomography of the TMJs highlighted a bilateral lesion with ankylosis of the left joint and of C1-C2. Surgical treatment consisted in block resection of the two TMJs using a cartilaginous rib. With a follow up of 9 months, results have been satisfactory., Discussion: Complementary explorations should be undertaken in ankylosing spondylitis patients with clinical symptoms suggestive of TMJ lesions in order to establish the diagnosis and initiate treatment and avoid the development of ankylosic forms.

Clinical presentation of temporomandibular joint (TMJ) disorders are more common in women and changes in the female hormone estrogen affect the level of swelling, pro-inflammatory cytokine release and pain in animal models of TMJ arthritis. Estrogen also modulates the expression of the CD16 receptor in vitro. This alters pro-inflammatory cytokine release in monocytes/macrophages when auto-antigens and arthritic factors bind the CD16 receptor. This study investigated the effects of various levels of estrogen on the intensity of inflammation and CD16 expression in a TMJ arthritic animal model. The experiments included rats that were intact or ovariectomized (OVX), eliminating the major source of estrogen output. A portion of the OVX animals had estrogen replaced with 17-beta estradiol (E2) using Alzet pumps. In OVX animals E2 levels were administered for 10 days to create an artificial estrus cycle or to simulate pregnancy. Following E2 treatment the rats were given an intra-articular TMJ injection of saline or complete Freund's adjuvant (CFA). CFA injection significantly increased TMJ swelling, stress induced chromodacryorrhea and attenuated food intake, thus indicating the adjuvant induced TMJ pain/inflammation. Removing endogenous E2 through OVX reduced CFA induced TMJ inflammation, whereas CFA increased the number of TMJ monocytes expressing the CD14 receptor equally in all groups irrespective of plasma E2 levels. Paradoxically, higher levels of E2 reduced the number of TNF-alpha positive, CD16+ and double labeled CD14+/CD16+ cells. The findings indicate that reduced plasma E2 levels attenuated CFA induced TMJ inflammation, whereas increasing E2 levels enhanced TMJ swelling in a dose dependent manner. Estrogenic group differences in CFA induced swelling were independent of TMJ CD14+, CD14+/CD16+ or CD16+ cell numbers suggesting E2 action on the CFA immune response primarily excluded CD16 receptor action.

Background: Synovitis, which is characterized by infiltration of inflammatory cells, often accompanies progression of clinical symptoms of the temporomandibular joint (TMJ). Synovial fibroblasts of the TMJ are believed to play important roles in progression of synovitis. The purpose of this study was to examine production and gene expression of chemokines by synovial fibroblasts stimulated by tumor necrosis factor-alpha (TNF-alpha)., Methods: Protein levels of chemokines were measured by enzyme-linked immunosorbent assay (ELISA). Gene expression of chemokines was analyzed by real-time polymerase chain reaction (PCR)., Results: Production of interleukin (IL)-8, growth-related oncogene (GRO)-alpha, monocyte chemoattractant protein (MCP)-1, and regulated upon activation normal T-cell expressed and secreted (RANTES) protein by synovial fibroblasts was increased by TNF-alpha. In contrast, stromal cell-derived factor (SDF)-1alpha, macrophage inflammatory protein (MIP)-1alpha and -1beta were not detectable in conditioned media of synovial fibroblasts, with or without TNF-alpha treatment. Increases in gene expression of IL-8, GRO-alpha, MCP-1, and RANTES in response to TNF-alpha treatment were detected., Conclusions: Increased protein production and gene expression of chemokines by synovial fibroblasts in response to TNF-alpha treatment appears to play an important role in recruitment of inflammatory cells into synovium and the progression of synovitis in the TMJ.

The aims were to investigate the effect of intravenous infusions of the tumor necrosis factor-alpha (TNF-alpha) antibody infliximab on symptoms and signs of temporomandibular joint (TMJ) involvement in relation to effects on synovial fluid and plasma proinflammatory TNF-alpha, interleukin-1beta (IL-1beta) and interleukin-6 as well as antiinflam matory soluble TNF receptor II (TNF-sRII), interleukin-1 receptor antagonist (IL-1ra), soluble IL-1 receptor II (IL-1sRII) and interleukin-10 (IL-10) in patients with active rheumatoid arthritis (RA). Nineteen patients with TMJ involvement taking methotrexate were included in the study. TMJ and general joint pain intensity as well as pain on mandibular movements, tenderness to digital palpation, pressure pain threshold and maximum mouth-opening capacity were assessed in a clinical examination. The effect of infliximab was assessed after 2 and 14 or 22 weeks. TMJ synovial fluid and venous blood were collected for cytokine analysis at all occasions while determination of erythrocyte sedimentation rate and C-reactive protein were performed at baseline and at long-term follow-up only. Reduction of TMJ pain was associated with raised levels of synovial fluid TNF-sRII and IL-1sRII as well as raised plasma levels of IL-1ra and IL-10. Decreased erythrocyte sedimentation rate was associated with decreased tenderness to digital palpation. Reduced general joint pain intensity was associated with reduced plasma levels of IL-6 and C-reactive protein. In conclusion, systemic treatment with a combination of infliximab and methotrexate reduces TMJ pain in RA in association with an increase in anti-inflammatory cytokines and receptors in synovial fluid and plasma., ((c) 2005 S. Karger AG, Basel)