Specific expression of substance P in synovial tissues of patients with symptomatic, non-reducing internal derangement of the temporomandibular joint: comparison with clinical findings

Our aim was to find out the extent of expression of substance P in synovial tissue from the human temporomandibular joints (TMJ) with symptomatic, non-reducing internal derangement, and to investigate the relationship between substance P and clinical findings. Fifty-four joints in 54 patients were examined immunohistochemically. Specimens of synovial tissue from 10 joints in 8 subjects with habitual dislocation of the TMJ with no pain were examined as controls. Cells that stained for substance P were found mainly among the endothelial cells in the blood vessels beneath the lining cells in synovial tissues from 47 of the 54 joints (87%) with internal derangement and from 5 of the 10 control joints. The extent score of cells that stained for substance P in joints with internal derangement was significantly higher than that in controls (p=0.02). The extent score of these cells did not correlate with pain in the joint or the degree of synovitis. These results suggest that substance P may have some roles in both the physiological and pathological conditions in patients with symptomatic internal derangement of the TMJ.     

Expression of interleukin 6 in synovial tissues in patients with internal derangement of the temporomandibular joint

Using an immunohistochemical technique, we examined synovial tissue from 46 temporomandibular joints (TMJ) with internal derangement in 44 patients. As controls, we examined synovial tissue specimens from 7 joints with habitual dislocation without pain. In synovial tissues from 21 of the 46 joints with internal derangement, interleukin 6 (IL-6) was expressed in the synovial lining cells and in the mononuclear cells infiltrating the periphery of the blood vessels. The density of IL-6-stained cells in specimens with internal derangement correlated significantly with the grade of joint effusion shown by magnetic resonance imaging (P=0.01, r=0.32).     

Relation between the expression of vascular endothelial growth factor in synovial tissues and the extent of joint effusion seen on magnetic resonance imaging in patients with internal derangement of the temporomandibular joint

The aim of this study is to elucidate the relation between the expression of vascular endothelial growth factor (VEGF) in synovial tissues and the extent of joint effusion seen on magnetic resonance imaging (MRI) in patients with internal derangement of the temporomandibular joint (TMJ). Using an immunohistochemical technique, we examined specimens of synovial tissues from 41 joints in 40 patients with internal derangement. Specimens from 36 of the 41 joints stained for VEGF. There was a significant correlation between the percentage of the VEGF-stained cells and the grade of joint effusion seen on MRI (P=0.0002, r=0.62). The correlation between the two was also significant on multiple logistic regression analysis (P=0.003, odds ratio=1.75). These results suggest that VEGF may have an important role in the genesis of joint effusion.     

The expression of vascular endothelial growth factor in synovial tissues in patients with internal derangement of the temporomandibular joint

OBJECTIVE: The aim of this study was to elucidate the expression and localization of vascular endothelial growth factor (VEGF) in synovial tissue taken from the temporomandibular joint (TMJ) with internal derangement (ID) and discuss the role of VEGF in the pathogenesis of ID. STUDY DESIGN: Through the use of an immunohistochemical technique, 39 TMJs in 37 patients were examined. As controls, synovial tissue specimens from 6 joints in 6 patients with habitual dislocation were also examined. RESULTS: In the synovial tissue from 35 of the patients with ID, expression of VEGF was observed in the synovial lining cells, in the endothelial cells of the blood vessels, and in the fibroblasts. In contrast, expression of VEGF was found in the TMJ tissue from only 2 of the controls. The percentage of VEGF-positive cells in the ID specimens was significantly higher than that in the habitual dislocation specimens (P < .02), and the expression of VEGF significantly correlated with the arthroscopic synovitis score (P = .004). CONCLUSION: These results suggest that the expression of VEGF is upregulated and involved in the development of inflammatory changes in synovial tissues in TMJs with ID.     

Temporomandibular joint pain: relationship to internal derangement type, osteoarthrosis, and synovial fluid mediator level of tumor necrosis factor-alpha

OBJECTIVES: The purpose of this study was to investigate whether patients with temporomandibular joint (TMJ)-related pain classified as capsulitis/synovitis may be linked to magnetic resonance imaging (MRI) findings of internal derangement, osteoarthrosis, or the synovial fluid aspirate findings of tumor necrosis factor-alpha (TNF-alpha) level. STUDY DESIGN: The study comprised 23 patients with temporomandibular disorders (TMD), who had nonchronic pain (pain onset < or =6 months) and a unilateral TMJ-related diagnosis of capsulitis/synovitis. Bilateral sagittal and coronal magnetic resonance images were obtained to establish the presence or absence of internal derangement, osteoarthrosis, or both. TMJ synovial fluid aspirates were obtained from the pain and contralateral nonpain sides to determine the TNF-alpha level. RESULTS: Comparison of the TMJ side-related data showed a significant relationship between the clinical TMD diagnosis of capsulitis/synovitis and the MRI diagnoses of TMJ internal derangement (P =.002) and of TMJ internal derangement type (P =.04). The mean TNF-alpha level in synovial fluid aspirates from TMJs assigned a clinical TMD diagnosis of capsulitis/synovitis was significantly higher than in those obtained from contralateral nonpain sides (P =.001). There was no correlation between the clinical diagnosis of capsulitis/synovitis and the MRI diagnosis of TMJ osteoarthrosis (P =.13) or between the MRI diagnosis of TMJ osteoarthrosis and that of TMJ internal derangement (P =.70) or TMJ internal derangement type (P =.33). CONCLUSIONS: The results suggest that the TMJ pain condition of capsulitis/synovitis is related to TMJ-side specific MRI diagnoses of internal derangement and internal derangement type, and synovial fluid aspirate findings of TNF-alpha level. The data confirm the concept of elevated mediator level as a diagnostic approach for patients presenting with TMJ-related pain. MRI and synovial fluid aspirates may be used as diagnostic methods for evaluating TMJ-related pain conditions.     

Immunohistochemical localization of inducible nitric oxide synthase in synovial tissue of human temporomandibular joints with internal derangement

The expression and distribution of inducible nitric oxide synthase (iNOS) was examined in 12 samples of human temporomandibular joint (TMJ) with internal derangement (ID) and four control specimens. In the diseased joints, strong or definite iNOS reactivity was expressed in synovial lining and endothelial cells; weaker activity was present in synovial fibroblasts. In contrast, although there was weak expression of iNOS in synovial fibroblasts and endothelial cells in the two control specimens, there was no iNOS staining in the synovial lining cell layers. This original report that iNOS is expressed in the synovial tissue of the temporomandibular joint indicates that nitric oxide is produced locally at least in the synovial lining in these joints when affected by internal derangement.     

Correlation between the arthroscopic diagnosis of synovitis and microvessel density in synovial tissues in patients with internal derangement of the temporomandibular joint.

OBJECTIVE: To elucidate the correlation between the arthroscopic diagnosis of synovitis and microvessel density in synovial tissues in patients with internal derangement of the temporomandibular joint (TMJ). STUDY DESIGN: Forty-three joints in 41 patients with internal derangement were examined and biopsies taken. Microvessel density was evaluated using the immunohistochemical method for CD 34 antibody. Arthroscopically diagnosed synovitis was evaluated according to Murakami's criteria. RESULTS: In patients with internal derangement, arthroscopically diagnosed synovitis scores averaged 5.2+/-2.0, according to Murakami et al. (1991). Small to large blood vessels were observed clearly with CD 34 stain. The mean microvessel density was 22.7+/-15.6 per two high power fields (magnification x200). Synovitis scores correlated significantly with microvessel density (p=0.002, r=0.43). CONCLUSION: Synovitis evaluated using Murakami's scores correlated well with the number of blood vessels in synovial tissues in patients with internal derangement of the TMJ. This demonstrates that synovitis is linked to inflammation-related blood vessel density of the synovial tissues.     

Levels of fibroblast growth factor 2 in synovial fluids in human patients with internal derangement of the temporomandibular joint

OBJECTIVE: We sought to elucidate the levels of fibroblast growth factor 2 (FGF-2) in synovial fluid taken from internally deranged human temporomandibular joints (TMJs) and to discuss the role of FGF-2 in the pathogenesis of internal derangement. STUDY DESIGN: Through the use of a pumping procedure, diluted synovial fluid was collected from the upper joint compartment of 22 TMJs with evidence of internal derangement (21 patients) and 8 TMJs with no such evidence (5 control subjects). Two of the control subjects were patients who had habitual dislocation, and three were healthy volunteers. The level of FGF-2 in the synovial fluid was assessed by means of an enzyme-linked immunosorbent assay. RESULTS: FGF-2 levels were at detectable levels in 15 of the 22 TMJs (68%) with internal derangement. The mean concentration of FGF-2 was 24 pg/mL. In the control group, FGF-2 levels were detectable in only 1 of 8 joints (13%), for a concentration of 3 pg/mL. The mean concentration of FGF-2 in the synovial fluid was significantly higher in the internal derangement group than in the control group (P =.02). CONCLUSIONS: FGF-2 levels are elevated in the human synovial fluid of TMJs with internal derangement.     

The expression of substance P in human temporomandibular joint samples: an immunohistochemical study

The expression of neuropeptide substance P was examined in 18 human temporomandibular joint (TMJ) samples with internal derangement of the TMJ, and in 10 control specimens. The examination was carried out using an immunohistological technique, using paraffin-embedded tissue and specific anti-human substance P polyclonal antibody. We noted five characteristic distribution patterns of substance P expression: at the nerves' fibre bundles in the connective tissues of the anterior and/or posterior attachment; around the blood vessels in the attachments; at the margin of the TMJ disc and synovial membrane layer; on the surface of hypertrophic synovial membranes with inflammation and proliferation; and around the newly formed capillaries in the TMJ discs. In TMJs with internal derangement associated with severe pain, we found distinct substance P expression in most of the specimens. The expression was particularly intense at the margin of the TMJ disc and synovial membrane layer, on the surface of hypertrophic synovial membranes and around the newly formed capillaries in the TMJ discs. The clinical symptoms of internal derangement of the TMJ are thought to be associated with the degree of synovitis. We conclude that the expression of substance P seems to be closely related to histopathological changes of the human TMJ with internal derangement.     

Does joint effusion on T2 magnetic resonance images reflect synovitis? Part 3. Comparison of histologic findings of arthroscopically obtained synovium in internal derangements of the temporomandibular joint

OBJECTIVES: To evaluate the relationship between the volume of joint effusion (JE), determined by T2-weighted magnetic resonance imaging (MRI), and microscopic findings of synovial inflammation in internal derangement of the temporomandibular joint (TMJ). STUDY DESIGN: Magnetic resonance images of 53 symptomatic TMJs (53 patients) associated with painful hypomobility were taken to evaluate the degree of JE on a scale of 0 to 3. Within 2 months after MRI, biopsy specimens obtained by arthroscopy were quantitatively assessed, on the basis of Gynther's grading system, for severity of hyperplasia of synovial lining cell layers, vascularity, and the presence of inflammatory cells. Each synovitis score was compared among the 4 JE grades, as well as between 2 groups-effusion present (grades 2 and 3) and effusion absent (grades 0 and 1)-by using the Spearman correlation coefficiency and the Mann-Whitney U test. RESULTS: The distribution of JE was as follows: 14 joints had grade 0, 9 joints had grade 1, 19 joints had grade 2, and 11 joints had grade 3. Significant relationships were found between the grades of JE and scores of synovial lining cell layers (P =.0012) as well as between the grades of JE and scores of presence of inflammatory cells (P =.0064). The joints with effusion had significantly higher scores for synovial lining cell layers (2.0 +/- 0.2) than the joints without effusion (1.3 +/- 0.2) (P =.029). There was no statistically significant correlation between the scores of vascularity and JE (P =.394). CONCLUSIONS: The evidence of JE on MRI might correlate with synovial inflammatory activity. It confirms the common consensus that JE probably reflects synovitis, especially when synovial hyperplasia has a key role in the pathogenesis of JE.     

Specific expression of interleukin-1 beta in temporomandibular joints with internal derangement: correlation with clinical findings.

OBJECTIVE: Interleukin-1 beta appears to play an important role in the pathophysiology of joint diseases. The aim of this study was to analyze the expression of interleukin-1 beta in temporomandibular joint internal derangement. STUDY DESIGN: Using an immunohistochemical technique with specific antibodies, we examined 20 human temporomandibular joint samples from patients with internal derangement of the temporomandibular joint: 5 extirpated disks and 15 biopsy specimens from the synovitic area of the temporomandibular joint upper compartment. We also examined 2 control specimens. The evaluation of interleukin-1 beta expression compared with clinical findings. RESULTS: Interleukin-1 beta was predominantly localized in the synovial lining cells and endothelial cells of blood vessels. Statistically significant correlation was found between interleukin-1 beta expression and some clinical findings. CONCLUSIONS: The results suggest that interleukin-1 beta may be involved in the pathogenesis of temporomandibular joint internal derangement and that the intensity of interleukin-1 beta expression may correlate with clinical findings, especially pain.     

Immunohistochemical localization of cyclooxygenase-1 and -2 in synovial tissues from patients with internal derangement or osteoarthritis of the temporomandibular joint

This study examined the immunohistochemical expression and localization of cyclooxygenase-1 and -2 (COX-1 and COX-2) in synovial tissues from patients with internal derangement (ID) or osteoarthritis (OA) of the temporomandibular joint (TMJ). Synovial tissues from patients with condylar fractures of the mandible were studied as control. Synovial tissues from 13 TMJs of 10 patients with ID or OA and from 5 TMJs of 4 patients with fractures were examined for COX-1 and COX-2 expression by immunohistochemical staining using two monoclonal antibodies. In addition, whether the COX-2 expression grade correlated with the synovitis score and clinical findings was assessed. COX-2 was expressed in the synovial lining, infiltrating mononuclear cells, fibroblast-like cells, and blood vessels, including CD31-positive endothelial cells, in the synovium of patients with ID or OA. Expression levels of COX-1 in synovial lining cells and endothelial cells were similar in the specimens obtained from the patients with ID or OA and those obtained from the controls. The expression of COX-2 positively correlated with arthroscopic findings of synovitis (p = 0.55, P = 0.023) and with joint pain (p = 0.56, P = 0.021). These results suggest that up-regulation of COX-2 in synovium may play a part in the pathogenesis of synovitis in patients with ID or OA of the TMJ.     

Bradykinin expression in synovial tissues and synovial fluids obtained from patients with internal derangement of the temporomandibular joint

Bradykinin has been implicated in the pathogenesis of inflammatory arthritis by virtue of the potent pro-inflammatory properties. The purpose of this study is to investigate the expression of bradykinin in patients with internal derangement of the temporomandibular joint (TMJ). We examined 33 TMJ synovial biopsy specimens from 31 patients with internal derangement of the TMJ by an immunohistochemical technique using specific antibodies. We also determined the concentration of bradykinin in 20 synovial fluids from 18 patients with TMJ internal derangement by enzyme-linked immunosorbent assay. These data were compared with those of the control subjects. Bradykinin was predominantly localized in the synovial lining cell layer of TMJ samples obtained from patients with TMJ internal derangement. Bradykinin was also detected in 19 patients' TMJ synovial fluids and the average of bradykinin concentration in the synovial fluids of patients was higher than that of the healthy controls. Although a statistically significant correlation was not observed, these findings support the hypothesis that bradykinin may also be involved in the pathogenesis of TMJ pain and synovitis.     

The immunohistochemical distribution of vimentin in human temporomandibular joint samples

The aim of this investigation was to evaluate the immunohistochemical distribution of vimentin in the temporomandibular joint (TMJ) and to compare it with the control specimens. Immunohistochemical distribution in the disc and synovial membrane in 30 human TMJ (internal derangement of TMJ, n = 20; and control, n = 10) was studied immunohistologically using paraffin-embedded tissue and specific anti-human vimentin monoclonal antibody. Vimentin expression was distributed in chondrocyte-like cells, synovial cells and endothelial cells. There was an obvious distinction of vimentin immunoreactivity between the control specimens and internal derangement cases, in the posterior and/or anterior loose connective tissues. In particular, intensive vimentin expression was detected in the hypertrophic synovial membrane of internal derangement cases. The findings of the present study suggest that vimentin might be an important marker of pathological hypertrophy of the synovial membrane and/or connective tissue with internal derangement of TMJ.     

Correlations of the expression of fibroblast growth factor-2, vascular endothelial growth factor,and their receptors with angiogenesis in synovial tissues from patients with internal derangement of the temporomandibular joint

Synovitis in internal derangement of the temporomandibular joint (TMJ) is accompanied by the growth of new blood vessels. Fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF) are well-characterized angiogenic factors. The objective of this study was to elucidate the correlation between the expression of FGF-2, VEGF, and their receptors-FGF receptor-1 (FGFR-1) and VEGF receptor-1 (Flt-1)-with microvessel density in synovial tissues of the TMJ. Using an immunohistochemical technique, we examined 47 joints (45 patients) with internal derangement. Individual microvessel density was evaluated by means of the CD34 antibody, a specific endothelial marker. The correlation between the percentage of immuno-positive cells and microvessel density was evaluated. In multiple logistic regression analysis, the correlation between the percentage of Flt-1-positive cells and microvessel density was significant [p = 0.005, odds ratio = 1.071, 95% confidence interval = 1.021-1.124]. These results suggest that the expression of the VEGF/Flt-1 system is involved in angiogenesis in inflamed synovial tissue in the TMJ.     

The expression of transforming growth factor beta (TGF-beta) in the synovial membrane of human temporomandibular joint with internal derangement: a comparison with tenascin expression

We examined the expression of the transforming growth factor beta (TGF-beta) in 28 human temporomandibular joint (TMJ) samples (internal derangement of TMJ and control specimens) by an immunohistological method using paraffin-embedded tissues and a polyclonal antibody specific to human TGF-beta. The resulting reaction of TGF-beta expression divided into three types as follows. The first type, around the fibrocyte and in the lacunae of chondrocytes in the disc. The second type, at the stroma of the mildly hypertrophic synovial membrane and severely hypertrophic synovial membrane. The first type was observed in all the cases including the control cases. The second type showed only in the internal derangement of TMJ, and its expression pattern resembled that of tenascin (TN) within the stroma of hypertrophic synovial membranes. In conclusion, TGF-beta and TN were distributed in the affected synovial membrane of TMJ with internal derangement. These findings suggested that TGF-beta and TN might have a close relationship with synovitis, followed by tissue repair.     

Association between arthroscopic diagnosis of temporomandibular joint osteoarthritis and synovial fluid nitric oxide levels.

OBJECTIVE: The purpose of this study was to determine whether there is a relationship between synovial fluid levels of nitric oxide and clinical and arthroscopic findings of synovitis or cartilaginous degeneration. STUDY DESIGN: Arthroscopic surgery was performed on 20 joints in 15 female patients with internal derangement and osteoarthritis of the temporomandibular joint. Synovial fluid aspirates were obtained immediately before arthroscopy. Synovial fluid was also obtained from 14 joints of 11 female asymptomatic volunteers. The concentration of nitrite in the fluid recovered from each temporomandibular joint was measured through use of a highly sensitive and specific chemiluminescence detection method, calibrated per 1 mg of synovial fluid protein and expressed as nitric oxide; the result was then compared with clinical and arthroscopic findings of synovitis and cartilaginous degeneration. RESULTS: Significantly higher levels of nitric oxide (median, 0.331 micromol/mg) were seen in the patients with internal derangement and osteoarthritis than in the control group (median, 0.001 micromol/mg; P<.0001). Synovial fluid from joints with pain in the joint area had significantly higher levels of nitric oxide than did fluid from joints without such pain. Synovial fluid from joints with degenerative changes (median, 0.467 micromol/mg) had significantly higher levels of nitric oxide than did fluid from joints without osteoarthritis (median, 0.057 micromol/mg; P<.05). Although the levels of nitric oxide in synovial fluid aspirates were markedly elevated in some joints with synovitis, there was no correlation between the levels of nitric oxide and the presence of synovitis. CONCLUSIONS: The findings indicate that increased levels of nitric oxide are involved in the pathogenesis of cartilaginous degeneration of the temporomandibular joint.     

Imaging temporomandibular joint abnormalities in patients with rheumatic disease. Comparison with surgical observations.

The preoperative examination findings in the soft tissue and bone of 22 temporomandibular joints of 15 patients with rheumatic disease were compared with the diagnosis after TMJ surgery. Agreement was found in 15 joints with rheumatic involvement and in 4 with internal derangement. In 5 (with unsuccessful arthrotomography) of the 15 rheumatic joints, magnetic resonance imaging showed destruction of disks with soft-tissue replacement, corresponding to fibrous tissue/ankylosis observed at surgery. Bony fusions in 2 of these joints were depicted with computed tomography. In the remaining 10 joints, arthrotomography showed irregularly outlined small compartments corresponding to synovial proliferations observed during surgery. Similar arthrotomographic interpretation, however, was made in 2 of 3 temporomandibular joints with imaging-surgery disagreement; surgery showed fibrous adhesions. In the third joint with unsuccessful arthrotomography, magnetic resonance imaging showed internal derangement but no synovial proliferations that were surgically observed. As experienced with other joints, synovial proliferations (or fibrous adhesions) could not be depicted with magnetic resonance imaging. Thus, differentiation between internal derangement with and without rheumatic involvement could be impossible with both arthrotomography and unenhanced magnetic resonance imaging.     

Vascular endothelial growth factor concentrations in synovial fluids of patients with symptomatic internal derangement of the temporomandibular joint

BACKGROUND: Vascular endothelial growth factor (VEGF) is an inducer of angiogenesis and permeability of small blood vessels. We determined the concentrations of VEGF in synovial fluid of patients with symptomatic internal derangement of the temporomandibular joint (TMJ). METHODS: Diluted synovial fluid was collected by a pumping procedure from 22 TMJs of patients with internal derangement and 10 control TMJs. VEGF concentration was determined by an enzyme-linked immunosorbent assay. RESULTS: The VEGF was detected in 14 of the 22 joints (64%) of patients with internal derangement, at a mean concentration of 67 pg/ml, but in only one control joint (12.5 pg/ml) (P = 0.004 for the difference in concentration). There was a significant correlation between VEGF concentration and total protein concentration in the synovial fluid (P = 0.002). CONCLUSIONS: The increased concentration of VEGF in patients with symptomatic internal derangement suggests that this growth factor may be involved in the pathogenesis of this condition.     

Bradykinin Expression in Synovial Tissues and Synovial Fluids Obtained from Patients with Internal Derangement of the Temporomandibular Joint

Bradykinin has been implicated in the pathogenesis of inflammatory arthritis by virtue of the potent pro-inflammatory properties. The purpose of this study is to investigate the expression of bradykinin in patients with internal derangement of the temporomandibular joint (TMJ). We examined 33 TMJ synovial biopsy specimens from 31 patients with internal derangement of the TMJ by an immunohistochemical technique using specific antibodies. We also determined the concentration of bradykinin in 20 synovial fluids from 18 patients with TMJ internal derangement by enzyme-linked immunosorbent assay. These data were compared with those of the control subjects. Bradykinin was predominantly localized in the synovial lining cell layer of TMJ samples obtained from patients with TMJ internal derangement. Bradykinin was also detected in 19 patients' TMJ synovial fluids and the average of bradykinin concentration in the synovial fluids of patients was higher than that of the healthy controls. Although a statistically significant correlation was not observed, these findings support the hypothesis that bradykinin may also be involved in the pathogenesis of TMJ pain and synovitis.