Degenerative Temporomandibular Joint Disease Research Articles

Nasal septum-derived chondroprogenitor cells control mandibular condylar resorption consequent to orthognathic surgery: a clinical trial.

Condylar resorption is an aggressive and disability form of temporomandibular joint (TMJ) degenerative disease, usually non-respondent to conservative or minimally invasive therapies and often leading to surgical intervention and prostheses implantation. This condition is also one of the most dreaded postoperative complications of orthognathic surgery, with severe cartilage erosion and loss of subchondral bone volume and mineral density, associated with a painful or not inflammatory processes. Because regenerative medicine has emerged as an alternative for orthopedic cases with advanced degenerative joint disease, we conducted a phase I/IIa clinical trial (U1111-1194-6997) to evaluate the safety and efficacy of autologous nasal septal chondroprogenitor cells. Ten participants underwent biopsy of the nasal septum cartilage during their orthognathic surgery. The harvested cells were cultured in vitro and analyzed for viability, presence of phenotype markers for mesenchymal stem and/or chondroprogenitor cells, and the potential to differentiate into chondrocytes, adipocytes, and osteoblasts. After the intra-articular injection of the cell therapy, clinical follow-up was performed using the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) and computed tomography (CT) images. No serious adverse events related to the cell therapy injection were observed during the 12-month follow-up period. It was found that autologous chondroprogenitors reduced arthralgia, promoted stabilization of mandibular function and condylar volume, and regeneration of condylar tissues. This study demonstrates that chondroprogenitor cells from the nasal septum may be a promise strategy for the treatment of temporomandibular degenerative joint disease that do not respond to other conservative therapies.

Radiological Aspects of Temporo-Mandibular Joint Osteoarthritis

This article is about applications of computed tomography (CT) in diagnosis of inflammatory and degenerative disease of temporomandibular joint (TMJ). CT is highly informative method forvisualization of disease of temporomandibular joint. Finally, sections on other aspects of CT research related to the TMJ, clinical decision-making and concluding remarks are added. However, it should be emphasized that the diagnostic information obtained is limited to the morphology of the osseous joint components, cortical bone integrity and subcortical bonedestruction/production. Author of this research studied the frequency of radiological signs in different age group. In addition, there were studied frequency of isolated, combination types, and more and less localization sitesof radiological patterns of inflammatory and degenerative changes of temporo-mandibular joint

Cone-beam computed tomographic characteristics in degenerative temporomandibular joint disease patients with chewing side preference

This study is aimed at assessing the Cone-beam computed tomographic (CBCT) characteristics of temporomandibular joints (TMJ) in degenerative temporomandibular joint disease (DJD) patients with chewing side preference (CSP). CBCT images of 98 patients with DJD (67 with CSP and 31 without CSP) and 22 asymptomatic participants without DJD were measured retrospectively to compare the osteoarthritic changes and the morphology of TMJ. Quantitative analysis of the TMJ radiographic images was performed to present a comparison between the three inter-group groups and between the two sides of the joints. The frequencies of the articular flattening and surface erosion occur more often in the preferred side joints of DJD patients with CSP than the contralateral side. In addition, the horizontal angle of condyle, the depth of glenoid fossa (DGF), and the inclination of articular eminence (IAE) were larger in DJD patients with CSP than that in asymptomatic participants (p<0.05). Also, the condylar anteroposterior dimension of preferred side joints was significantly less than that of non-preferred side (p=0.026), while the width of condyles (p=0.041) and IAE (p=0.045) was greater. DJD patients with CSP appear to have a higher prevalence of osteoarthritic changes, with the morphological changes such as flat condyle, deep glenoid fossa, and steep articular eminence, which might be considered the characteristic imaging features. This study found that CSP is a predisposing factor for the development of DJD, and attention should be paid to the existence of CSP in DJD patients during the clinical practice.

Short term effects of a novel combined approach compared with physical therapy alone among older patients with temporomandibular degenerative joint disease: a prospective cohort study

BackgroundThere is a lack of consensus regarding the best treatment option, including physical exercise, available for temporomandibular degenerative joint disease (DJD) that affect the older patients. Herein, we aimed to study and compare the efficacy of a combined approach using injection and home physical exercise with physical therapy alone as well as explored an optimal treatment strategy for older patients with DJD.MethodsWe included 213 older patients with DJD treated at our medical centre from June 2020 to June 2021, 64 of whom were selected for analysis. Of these 64 patients, 32 received injections combined with home physical exercise, and the other 32 received physical therapy alone. Propensity score matching was used to ensure that the two groups did not differ significantly in categorical and continuous variables. Measurements included pain intensity, maximum mouth opening, joint crepitus, jaw functional limitation scale (JFLS) scores, treatment times, and treatment durations. Improvement in each measurement was compared between the two groups 2, 4, and 12 weeks after the treatment commenced, as were the final treatment times and durations.ResultsPain intensity, maximum mouth opening, and JFLS scores in the two groups improved 2, 4, and 12 weeks after treatment (all p < 0.05). The crepitus ratio improved significantly only in the combined treatment group after 12 weeks. Compared with the physical therapy group, pain while opening the mouth improved after 2, 4, and 12 weeks in the combined treatment group. Furthermore, 2 weeks after treatment, the physical therapy group showed significant improvement in maximal mouth opening compared with the combined treatment group. No significant between-group differences were observed regarding improvement in joint crepitus and JFLS scores at each observation point. The combined treatment group had a significantly lower number of visits than the physical therapy group; however, the treatment duration was longer.ConclusionCompared with physical therapy, pain while opening the mouth is significantly improved by the combined treatment within 12 weeks, and the number of required visits is fewer. Physical therapy improves the patients’ mouth-opening capabilities in a short time (2 weeks), and the treatment cycle is short.

Differences in clinical and radiographic features between bilateral and unilateral adult degenerative temporomandibular joint disease: A retrospective cross-sectional study

To study the correlations of clinical findings and the severity of osseous alterations between bilateral and unilateral degenerative joint disease (DJD) of the temporomandibular joint (TMJ). Forty-eight joints from 35 adult patients with DJD were retrospectively examined. The joints were divided into two groups: bilateral DJD (BDJD) (26 joints) and unilateral DJD (UDJD) (22 joints). We collected data on patient characteristics and symptoms, including pain on palpation, limited mouth opening, pain during mandibular movement, and joint noises. Cone beam Computed Tomography (CBCT) was used to assess bony changes, including maximum condylar bone change, severity of erosion, severity of osteophytes, glenoid fossa changes, and superior joint space measurements. Data were correlated between subgroups. There was no significant difference between the two groups in terms of age or gender. However, pain on palpation was significantly more common in UDJD joints (81.8%) compared to BDJD joints (53.9%). Limitation of mouth opening was also significantly more common in BDJD cases (61.5%) compared to UDJD cases (22.7%). The number of joints with painless degeneration was more common in BDJD TMJs (38.4%) than in UDJD TMJs (9%). There was no significant difference between the two subgroups with regard to pain during mandibular movements or joint sounds and severity of bony changes. This study provided important results outlining clinical the clinical profiles of DJD patients. While painful degeneration was more frequent in UDJD joints, painless degeneration was higher in BDJD joints. Limitation of mouth opening was more common in BDJD patients.

Diagnostic performance of magnetic resonance imaging for degenerative temporomandibular joint disease.

Degenerative joint disease (DJD) of the temporomandibular joint (TMJ) is an important type of temporomandibular disorders (TMDs) potentially leading to orofacial pain and jaw dysfunction. Magnetic resonance imaging (MRI) is important in TMD diagnosis; however, its diagnostic ability for DJD remains unknown. To explore the utility of MRI in diagnosing DJD according to the latest diagnostic criteria for TMD and detecting condylar bone abnormalities and their severity. Overall, 122 participants were examined using cone-beam computed tomography (CBCT) and MRI. The sensitivity, specificity and accuracy of MRI for detecting DJD and different types of TMJ condylar bone abnormalities were calculated (considering CBCT as gold standard); in addition, we tested MRI and CBCT's consistency in scoring five types of condylar bone abnormalities. The sensitivity and specificity of MRI for DJD were 95.3% and 43.1%, respectively. The MRI sensitivities for condylar flattening, erosion, osteophytes, sclerosis and cysts were 98.6%, 96.2%, 79.4%, 50%, and 79.2% (specificity, 53.6%, 48.3%, 81.6%, 83.3%, and 88.2%, respectively), respectively. The consistency between MRI and CBCT in assessing the severity of condylar bone abnormalities was fair-to-moderate (kappa coefficient: 0.278-0.491). The inter-observer consistency for CBCT was good, whereas for MRI, it was relatively poor. MRI can detect DJD and condylar bone abnormalities. However, MRI could not efficiently detect the severity of condylar bone abnormalities.

Comparison of two different therapeutic approaches for skeletal Class II patients with temporomandibular degenerative joint disease.

To compare two different therapeutic approaches for skeletal Class II patients with temporomandibular degenerative joint disease. A total of 47 patients were included in this study. Group anterior repositioning splint (ARS) was treated with temporomandibular joint (TMJ) disc surgery followed by an ARS and camouflage orthodontic treatment. Group stabilization splint (SS) was treated with an SS followed by orthodontic treatment combined with orthognathic surgery. Cephalometric analysis of lateral radiographs and measurements of condylar height were evaluated before and after splints. In group ARS, mandibular advancement was observed after treatment in 21 of 24 patients (87.5%). The SNB angle increased by an average of 1.40 ± 1.01°. The ANB angle, overjet, Wits, and convexity decreased. Facial angle and soft tissue N Vert to pogonion increased. Vertically, MP-FH, MP-SN, y-axis, and vertical ratio decreased and ANS-Me/N-Me and S-Go/N-Me increased, suggesting a counterclockwise rotation of the mandible. In group SS, 18 of 23 patients (78.3%) showed a backward change tendency. The SNB angle reduced by 0.90 ± 0.93°. The ANB angle, overjet, Wits, convexity, and y-axis increased. The facial angle and soft tissue N Vert to soft tissue pogonion (ST N Vert to ST pogonion) decreased. Magnetic resonance imaging showed condylar height increased by 1.45 ± 3.05 mm (P = .002) in group ARS. In group SS, condylar height change was not consistent. TMJ disc surgery followed by ARS promoted condylar bone remodeling and regeneration. The SNB angle increased, and the severity of skeletal Class II was improved. The SS enabled the mandible to withdraw backward and revealed a retrognathic but true mandible position.

Correctly distinguish osteoarthrosis and osteoarthritis in temporomandibular joint degenerative disease

Temporomandibular joint degenerative disease is a common disease in the temporomandibular joint disorders, including osteoarthrosis and osteoarthritis. There were often confused in clinical diagnosis, treatment and basic research both of osteoarthrosis and osteoarthritis. That will affect the choice of clinicians and scientists to the treatment of disease, the judgment of prognosis, and the experimental results. The key to distinguishing the clinical significance of osteoarthrosis and osteoarthritis in temporomandibular degenerative disease lies in how to correctly recognize the main differences between the two, that is, whether there is pain in the temporomandibular joint and the masticatory muscle area. At the same time, it is necessary to judge the course of the disease, whether the two are transforming each other and the clinical significance of other dentistry.

Effects of patient education on the oral behavior of patients with temporomandibular degenerative joint disease: a prospective case series study

ABSTRACT Objective To evaluate the effects of patient education and related factors on oral behaviors (OBs) in patients with temporomandibular joint degenerative diseases. Methods Sixty-three patients were included. Temporomandibular joint specialists conducted clinical examinations, provided patient education, and administered the Oral Behavior Checklist (OBC) questionnaire at baseline. Patients were followed up at 6 months. Results Eight OBs showed a high incidence among patients. At the 6-month follow-up, the incidence of 6 of the OBs decreased, all of which were high incidence OBs. The frequency of 9 OBs decreased, of which 8 were high incidence OBs. The average OBC score decreased from 22.97 ± 9.30 to 17.90 ± 9.28. Age, education level, and original OBC score had a significant effect on OB improvement. Conclusion Patient education and the corresponding treatment are conducive to OB improvement. The related factors affecting the improvement in patients’ OBs were age, education level, and OB severity.

Functional, physical and psychosocial impact of degenerative temporomandibular joint disease.

This study evaluated the functional, physical and psychosocial impacts of TMJ degenerative joint disease (DJD). The bearing of TMJ osteoarthrosis/osteoarthritis and early/late TMJ DJD on oral health-related quality of life (OHRQoL) were also compared. Participants were enrolled from a TMD/oro-facial pain centre. Those diagnosed with intra-articular conditions based on the Diagnostic Criteria for Temporomandibular disorders (DC/TMD) were subjected to CBCT assessment and categorised into four discrete groups: NN-no TMJ DJD and no arthralgia; NA-no TMJ DJD with arthralgia; TO-TMJ osteoarthrosis; and TR-TMJ osteoarthritis. The TO/TR groups were subdivided into early/late TMJ osteoarthrosis (EO/LO) and osteoarthritis (ER/LR). OHRQoL was examined using the OHIP-TMD, and data were appraised with the Kruskal-Wallis/Mann-Whitney U tests (α=0.05). The study participant (n=358) had a mean age of 31.85±12.39years (85.6% women). Frequencies of the TMD groups were as follows: NN-23.2%; NA-27.1%; TO-19.0%; and TR-30.7%. Participants with TR/NA had significantly worse OHRQoL than those with TO/NN. Additionally, participants with ER/LR reported significantly poorer OHRQoL than their counterparts with EO/LO. For all TMD groups and TMJ DJD subgroups, the psychological discomfort domain was generally the most impaired. Differences in global OHIP scores were significant between participants with and without arthralgia (i.e., NA-NN, ER-EO and LR-LO). The presence of TMJ pain appeared to impair OHRQoL more than the severity of TMJ DJD. As psychological domains were most impacted, psychosocial care should be incorporated when managing patients with painful TMJ DJD.

Radiographic interpretation using high-resolution Cbct to diagnose degenerative temporomandibular joint disease.

The objective of this study was to use high-resolution cone-beam computed images (hr- CBCT) to diagnose degenerative joint disease in asymptomatic and symptomatic subjects using the Diagnostic Criteria for Temporomandibular Disorders DC/TMD imaging criteria. This observational study comprised of 92 subjects age-sex matched and divided into two groups: clinical degenerative joint disease (c-DJD, n = 46) and asymptomatic control group (n = 46). Clinical assessment of the DJD and high-resolution CBCT images (isotropic voxel size of 0.08mm) of the temporomandibular joints were performed for each participant. An American Board of Oral and Maxillofacial Radiology certified radiologist and a maxillofacial radiologist used the DC/TMD imaging criteria to evaluate the radiographic findings, followed by a consensus of the radiographic evaluation. The two radiologists presented a high agreement (Cohen's Kappa ranging from 0.80 to 0.87) for all radiographic findings (osteophyte, erosion, cysts, flattening, and sclerosis). Five patients from the c- DJD group did not present radiographic findings, being then classified as arthralgia. In the asymptomatic control group, 82.6% of the patients presented radiographic findings determinant of DJD and were then classified as osteoarthrosis or overdiagnosis. In conclusion, our results showed a high number of radiographic findings in the asymptomatic control group, and for this reason, we suggest that there is a need for additional imaging criteria to classify DJD properly in hr-CBCT images.

Interexaminer reliability for tomographic findings in temporomandibular joint degenerative disease and its agreement with clinical diagnosis: a blinded controlled cross sectional study

The aim of this study was to evaluate the interexaminer reliability for tomographic findings in degenerative temporomandibular joint disease and its agreement with clinical diagnosis. Women aged 18 and 60years were invited to participate in this research. All participants were evaluated by a single experienced examiner according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Group 1 was comprised of TMJs with Degenerative Joint Disease (DJD). Group 2 was comprised of healthy TMJs, without any signs and/or symptoms of TMD. All CBCT images were evaluated by 2 calibrated examiners for the image evaluation criteria but blinded for the clinical diagnosis. From the 194 women evaluated, 41 were included, with a mean age of 35.23 (± 14.06) years. Group 1 was comprised of 26 TMJs with DJD and group 2 of 36 asymptomatic TMJs. The interexaminer reliability was κ = 0.706 (p < 0.000), while agreement between clinical and tomographic findings were κ = 0.301 (p = 0.01) and κ = 0.273 (p = 0.02) for each examiner. The use of CBCT as a diagnostic test had shown sensitivity and specificity values of 61.5% and 75%, respectively. The interexaminer reliability for tomographic findings was strong. However, the agreement between clinical and tomographic findings was reasonable, for both examiners.

Management of Septic Arthritis of the Temporomandibular Joint in Dogs.

Septic arthritis of the temporomandibular joint (TMJ) in dogs and other mammals is a rare condition. It is typically associated with notable pain, swelling, and difficulty in opening the mouth. Unlike degenerative TMJ disease, septic arthritis requires urgent intervention. The etiology of the condition may include penetrating trauma, an extension of local infection, such as otitis media, or the hematogenous spread of a pathogen. However, the precise cause may not always be identified. Diagnostic imaging with Computed Tomography (CT), cone-beam CT (CBCT), and/or Magnetic Resonance Imaging (MRI) are helpful for honing the definitive diagnosis and formulating a treatment plan. Subsequently, exploratory surgery may be required to obtain samples for culture and sensitivity and histology and to lavage the joint. In this “methods” article, we provide a detailed description of our approach to diagnosis and management of septic TMJ arthritis in four dogs.

Increased chemokine RANTES in synovial fluid and its role in early-stage degenerative temporomandibular joint disease.

Degenerative joint disease (DJD) of the temporomandibular joints (TMJs) in adolescents and young adults is closely associated with disc displacement without reduction (DDw/oR). This study aimed to determine the pathogenesis of early-stage TMJ DJD induced by DDw/oR. 31 female subjects aged 12-30years were enrolled, comprising 12 patients with DDw/oR without DJD, 13 with DDw/oR and early-stage DJD, and 6 healthy volunteers. The synovial fluid samples of the subjects were screened for 27 inflammatory-related cytokines using multiple cytokine array. Significantly increased cytokines and a key regulator of osteoclastogenesis "receptor activator of nuclear factor-κB ligand" (RANKL) were further determined by sandwich immunoassay. These factors were also assessed for the possible pathophysiologic actions on RAW264.7 cell proliferation, migration, osteoclastogenesis and bone-resorbing activity using Cell Counting Kit-8, Transwell system, tartrate-resistant acid phosphatase staining and osteo assay plates. Macrophage-derived inflammatory protein-1 beta (MIP-1β) and regulated upon activation normal T cell expressed and secreted (RANTES) were found to vary significantly in relation to the controls. In contrast to an unchanged concentration of RANKL, a strong increase in the level of RANTES was detected in subjects with DDw/oR and early-stage DJD. MIP-1β concentrations were only elevated in subjects with DDw/oR without DJD. Functionally, both MIP-1β and RANTES could enhance macrophage migration in a concentration-dependent manner, while only RANTES exhibited a promoting effect on osteoclast formation and bone-resorbing activity. Chemokine RANTES was significantly upregulated and might be a key regulator of osteoclastogenesis contributing to DDw/oR-induced early-stage TMJ DJD.

Radiological value of computed tomography in degenerative disease of temporomandibular joint

Radiological value of computed tomography in degenerative disease of temporomandibular joint

Are Signs of Degenerative Joint Disease Associated With Chin Deviation?

Degenerative joint changes commonly affect the temporomandibular joint (TMJ) and can result in chin deviation. However, the extent of degenerative TMJ changes and chin deviation has not been well-characterized. The present study sought to correlate degenerative TMJ changes with condylar volume, grayscale measures, and chin deviation. The present cross-sectional study had enrolled women with skeletal Class III malocclusion. Cone-beam computed tomography scans were acquired preoperatively. For each condyle, degenerative TMJ signs were analyzed and the condylar volume and grayscale were measured. The predictor variable was the presence of degenerative TMJ signs, classified as categorical data: 0, if none; 1, only present in 1 joint; and 2, present in both joints. The primary outcome variable was a chin deviation of 3mm or more. Other associated variables were grouped by age, cephalometric data, and 3-dimensional condylar measurements. Descriptive bivariate statistics were computed, and univariate and multiple logistic regression analyses were conducted to identify any associations between degenerative TMJ disease and chin deviation. We included 85 patients, who were classified into 2 groups: less than 3mm of chin deviation (n=43) and 3mm or more of chin deviation (n=42). The presence of more than 10 degenerative TMJ signs was significantly associated with the presence of 3mm or more of chin deviation (P<.001). In multiple regression models, the presence of subcortical sclerosis in 1 joint and in both joints (adjusted odds ratio [OR], 3.698; 95% confidence interval [CI], 1.051 to 13.012; adjusted OR, 5.001; 95% CI, 1.461-17.119, respectively) correlated significantly with the presence of 3mm or more of chin deviation (P<.05). The volume difference between the 2 condyles was significantly greater in the group with more than 10 degenerative TMJ signs and 3mm or more of chin deviation than in the group with 10 or fewer degenerative TMJ signs and less than 3mm of chin deviation (P=.016 and P<.001, respectively). In women with skeletal Class III malocclusion, the presence of more than 10 degenerative TMJ signs increased the prevalence of 3mm or more of chin deviation. The presence of subcortical sclerosis in either 1 or both joints and volume differences between the 2 condyles were associated with greater chin deviation.

Condylar repair and regeneration in adolescents/young adults with early-stage degenerative temporomandibular joint disease: A randomised controlled study.

Anterior repositioning splint (ARS) can facilitate regenerative condylar remodelling. To determine the effect of ARS on osseous condylar changes in adolescents/young adults with early-stage degenerative joint disease (DJD). Sixty-nine patients with early-stage temporomandibular joint (TMJ) DJD based on the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) and cone beam computed tomography (CBCT) imaging were recruited and randomly allocated to two treatment groups: (a) conservative therapy with ARS and (b) conservative therapy without ARS. Subjects with acute TMJ closed-lock had their displaced discs physically reduced by mandibular manipulation prior to ARS therapy. Clinical and CBCT data of 59 patients (86.4% females, mean age 17.95±4.53years, 67 joints) were attained pre- and at 6 or 12months post-treatment. Osseous changes after treatment were categorised into (a) progressed, (b) unchanged, (c) repaired (remodelled without new bone formation) and (d) regenerated (remodelled with new bone formation). Statistical analysis including chi-square test, independent samples t test or Mann-Whitney U test was conducted. About 85.5% of patients (59/69) completed the study, with 28 subjects (32 joints) in the splint group and 31 (35 joints) in the control group. The occurrence of condylar repair and regeneration was significantly higher with ARS (78.1%/[25/32] of joints) when compared to control group (48.6%/[17/35]) (P<0.05). Moreover, condylar regeneration was exclusively observed in 50%/(16/32) of joints with ARS. For the 14 joints in splint group that received physical TMJ closed-lock reduction, 85.7%/(12/14) exhibited condylar regeneration. The splint group (3.1%/[1/32]) also had significantly lower incidence of progressive TMJ degeneration than the control (37.1%/[13/35]) (P<0.001). Condylar repair and regeneration in early-stage TMJ DJD are possible, and ideal spatial disc-condyle relationship appears important. The possibility of restoring TMJ form/structure by ARS therapy presents an attractive area of new basic science and clinical research (Bone defect repair in early osteoarthrosis of temporomandibular joint by joint distraction therapy: A randomized controlled trial/ChiCTR-TRC-14005172).

The Clinical Efficacy of Injectable Platelet Rich Fibrin in the Treatment of Degenerative Temporomandibular Joint Disease

The Clinical Efficacy of Injectable Platelet Rich Fibrin in the Treatment of Degenerative Temporomandibular Joint Disease

Estrogen Promotes Mandibular Condylar Fibrocartilage Chondrogenesis and Inhibits Degeneration via Estrogen Receptor Alpha in Female Mice

Temporomandibular joint degenerative disease (TMJ-DD) is a chronic form of TMJ disorder that specifically afflicts people over the age of 40 and targets women at a higher rate than men. Prevalence of TMJ-DD in this population suggests that estrogen loss plays a role in the disease pathogenesis. Thus, the goal of the present study was to determine the role of estrogen on chondrogenesis and homeostasis via estrogen receptor alpha (ERα) during growth and maturity of the joint. Young and mature WT and ERαKO female mice were subjected to ovariectomy procedures and then given placebo or estradiol treatment. The effect of estrogen via ERα on fibrocartilage morphology, matrix production, and protease activity was assessed. In the young mice, estrogen via ERα promoted mandibular condylar fibrocartilage chondrogenesis partly by inhibiting the canonical Wnt signaling pathway through upregulation of sclerostin (Sost). In the mature mice, protease activity was partly inhibited with estrogen treatment via the upregulation and activity of protease inhibitor 15 (Pi15) and alpha-2-macroglobulin (A2m). The results from this work provide a mechanistic understanding of estradiol on TMJ growth and homeostasis and can be utilized for development of therapeutic targets to promote regeneration and inhibit degeneration of the mandibular condylar fibrocartilage.

17β-estradiol Induces MMP-9 and MMP-13 in TMJ Fibrochondrocytes via Estrogen Receptor α

Temporomandibular joint (TMJ) disorders, including degenerative TMJ disease, occur primarily in women of reproductive age. Previous studies showed elevated estrogen levels in subjects with TMJ disorders relative to controls and the presence of estrogen receptors α and β (ERα and ERβ) in TMJ fibrocartilage. Additionally, estrogen-induced overexpression of specific matrix metalloproteinases (MMPs), including MMP-9 and MMP-13, in TMJ fibrocartilage is accompanied by loss of extracellular matrices. However, the contribution of ERα and ERβ in estrogen-mediated induction of MMP-9 and MMP-13 and the signaling cascade leading to the upregulation of these MMPs have not been elucidated. Here, we show that specific siRNAs and selective ER antagonists effectively block ERα or ERβ expression in primary mouse TMJ fibrochondrocytes, but that only blockage of ERα suppresses MMP-9 and MMP-13 levels induced by 17β-estradiol (E2). Overexpression of ERα but not ERβ enhances E2-induced MMP-9. Using the same loss-of-function and gain-of-function approaches, we demonstrate that E2 stimulates ERK activation through ERα and that inhibition of ERK phosphorylation reduces E2-induced MMP-9. Furthermore, we reveal that E2 promotes NF-κB and ELK-1 activation through ERα/ERK signaling and that knockdown of either one decreases the respective activity of these signaling mediators and MMP-9 expression induced by E2, indicating that both contribute to E2/ERα/ERK-mediated MMP-9 upregulation. This is supported by findings in which mutated binding sites of either NF-κB or ELK-1 in the MMP-9 promoter lead to a significant reduction of E2-stimulated promoter activity. Our findings provide novel molecular mechanisms for the understanding of E2-mediated upregulation of MMPs, having implications to pathophysiologic TMJ cartilage matrix turnover that may yield therapeutic intervention targets for TMJ disorders.