Medication-related osteonecrosis of the jaw after tooth extraction in cancer patients: a multicenter retrospective study.

Root amputation, immunosuppressive therapy, mandibular tooth extraction, pre-existing inflammation, and longer duration of treatment with bone-modifying agents were significantly associated with an increased risk of medication-related osteonecrosis of the jaw. Hopeless teeth should be extracted without drug holiday before the development of inflammation in cancer patients receiving high-dose bone-modifying agents. INTRODUCTION: No studies have comprehensively analyzed the influence of pre-existing inflammation, surgical procedure-related factors such as primary wound closure, demographic factors, and drug holiday on the incidence of medication-related osteonecrosis of the jaw (MRONJ). The purpose of this study was to retrospectively investigate the relationships between these various factors and the development of MRONJ after tooth extraction in cancer patients receiving high-dose bone-modifying agents (BMAs) such as bisphosphonates or denosumab. METHODS: Risk factors for MRONJ after tooth extraction were evaluated with univariate and multivariate analyses. The following parameters were investigated in all patients: demographics, type and duration of BMA use, whether BMA use was discontinued before tooth extraction (drug holiday), the duration of such discontinuation, the presence of pre-existing inflammation, and whether additional surgical procedures (e.g., incision, removal of bone edges, root amputation) were performed. RESULTS: We found that root amputation (OR = 22.62), immunosuppressive therapy (OR = 16.61), extraction of mandibular teeth (OR = 12.14), extraction of teeth with pre-existing inflammation, and longer duration (≥ 8 months) of high-dose BMA (OR = 7.85) were all significantly associated with MRONJ. CONCLUSIONS: Tooth extraction should not necessarily be postponed in cancer patients receiving high-dose BMA. The effectiveness of a short-term drug holiday was not confirmed, as drug holidays had no significant impact on MRONJ incidence. Tooth extraction may be acceptable during high-dose BMA therapy until 8 months after initiation.

Effect of interleukin-1beta and dehydroepiandrosterone on the expression of lumican and fibromodulin in fibroblast-like synovial cells of the human temporomandibular joint.

Several epidemiological studies have reported that temporomandibular disorders (TMDs) are more prevalent in women than in men. It has recently been proposed that sex hormones such as estrogen, testosterone and dehydroepiandrosterone (DHEA) are involved with the pathogenesis of TMDs. Although studies have investigated the relationship between estrogen and testosterone and the restoration of TMDs, the relationship between DHEA and TMDs is unknown. The synovial tissue of the temporomandibular joint (TMJ) is made up of connective tissue with an extracellular matrix (ECM) composed of collagen and proteoglycan. One proteoglycan family, comprised of small leucine-rich repeat proteoglycans (SLRPs), was found to be involved in collagen fibril formation and interaction. In recent years, the participation of SLRPs such as lumican and fibromodulin in the internal derangement of TMJ has been suggested. Although these SLRPs may contribute to the restoration of the synovium, their effect is still unclear. The purpose of this study was to investigate the effect of DHEA, a sex hormone, on the expression of lumican and fibromodulin in human temporomandibular specimens and in cultured human TMJ fibroblast-like synovial cells in the presence or absence of the pro-inflammatory cytokine interleukin-1beta (IL-1beta). In the in vivo study, both normal and osteoarthritic (OA) human temporomandibular synovial tissues were immunohistochemically examined. In the in vitro study, five fibroblast-like synoviocyte (FLS) cell lines were established from human TMJ synovial tissue of patients with osteoarthritis. The subcultured cells were then incubated for 3, 6, 12 or 24 h with/without IL-1beta (1 ng/mL) in the presence or absence of DHEA (10 µM). The gene expression of lumican and fibromodulin was examined using the real-time polymerase chain reaction (PCR) and their protein expression was examined using immunofluorescent staining. We demonstrated that the expression of lumican significantly differs from that of fibromodulin in synovial tissue in OA and furthermore, that IL-1beta induced a significant increase in lumican mRNA and immunofluorescent staining in FLS compared to cells without IL-1beta. DHEA plus IL-1beta induced a significant increase in fibromodulin, but not in lumican mRNA, compared to DHEA alone, IL-1beta alone and in the absence of DHEA and IL-1beta. In immunofluorescent staining, weaker fibromodulin staining of FLS cells was observed in cells cultured in the absence of both DHEA and IL-1beta compared to fibromodulin staining of cells cultured with DHEA alone, with DHEA plus IL-1beta, or with IL-1beta alone. These results indicate that DHEA may have a protective effect on synovial tissue in TMJ by enhancing fibromodulin formation after IL-1beta induced inflammation. DHEA enhancement of fibromodulin expression may also exert a protective effect against the hyperplasia of fibrous tissue that TGF-beta1 induces. In addition lumican and fibromodulin are differentially expressed under different cell stimulation conditions and lumican and fibromodulin may promote regeneration of the TMJ after degeneration and deformation induced by IL-1beta.

Synovial chondromatosis of the temporomandibular joint: clinical and immunohistopathological considerations.

A histopathological study of 30 cases of synovial osteochondromatosis found that the process followed a temporal sequence characterised by three phases: (I) active intrasynovial disease only; (II) transitional lesions with both active intrasynovial proliferation and free loose bodies; and (III) many free osteochondral bodies with no demonstrable intrasynovial disease [J. Bone Joint Surg. 59 (1977) 792]. We present five cases of synovial chondromatosis of the temporpmandibular joint (TMJ) which we studied by immunohistochemical methods of for transforming growth factor beta (TGFbeta) and tenascin.

Inhibition of fibrous adhesion formation in the temporomandibular joint of tenascin-C knockout mice.

Tenascin-C (TNC) is a large hexameric extracellular matrix glycoprotein that is expressed in developing organs and tumors. It has been reported that TNC is expressed in inflamed synovial membranes and deformed discs of temporomandibular joint (TMJ) disorder. However, the role of TNC in TMJ is not fully known. In this study, the role of TNC in fibrous adhesion formation of TMJ was examined using TNC knockout (TNCKO) mice. Hypermobility was produced by excessive mouth opening method on the TMJ of both wild-type (WT) and TNCKO mice. TMJ wound healing was compared histologically, and the expression of TNC, fibronectin (FN) and α-smooth muscle actin (α-SMA) in the wounded TMJ was examined by immunohistochemical and immunoblot analyses. Based on histologic analysis, fibrous adhesions were observed in the TMJ of both TNCKO and wild-type (WT) mice after excessive mouth opening. However, fibrous adhesion formation in TNCKO mice occurred later than in WT mice. TNC was expressed in the wounded TMJ disc and mandibular fossa. Although FN and α-SMA expression in the TMJ of TNCKO and WT mice was up-regulated after excessive mouth opening, FN and α-SMA protein levels were higher in WT mice at the same time points. In the wounded TMJ, TNC appears to enhance the expression of FN and α-SMA, and a lack of TNC may reduce fibrous adhesion formation in the TMJ. TNC plays an important role in TMJ wound healing, especially for wounds generated by mechanical stress.

Expression of lumican and fibromodulin following interleukin-1 beta stimulation of disc cells of the human temporomandibular joint.

Small leucine-rich repeat proteoglycans (SLRP) are present in the extracellular matrix of the temporomandibular joint (TMJ) disc. Lumican and fibromodulin, classified as class 2 SLRPs, play important roles in TMJ assembly, proliferation and inflammation. Degenerative change in the TMJ disc gives rise to the process of internal derangement (ID). In this study, we immunohistochemically examined the expression of lumican and fibromodulin in nine human TMJ specimens and examined the gene expression of both proteoglycans in cultured human TMJ disc cells under interleukin-1 beta (IL-1 ß)-stimulated conditions. An articular disc cell line was established by collagenase treatment of a TMJ disc. The subcultured cells were then incubated for 1, 3, 6, 12, 24 or 48 h under both normal and IL-1 ß (1 ng/mL) conditions. The gene expression of lumican and fibromodulin was examined using the reverse transcription-polymerase chain reaction (RT-PCR) and real-time RT-PCR. We demonstrated that the expression of lumican significantly differs from that of fibromodulin in the deformed disc and that IL-1 ß induces a significant increase in lumican mRNA, but not in fibromodulin mRNA, after 24∼48 h culture compared to cells cultured in the absence of IL-1 ß (P<0.05). These results indicate that lumican and fibromodulin display different behaviors and that lumican may promote regeneration of the TMJ after degeneration and deformation induced by IL-1 ß.

Expression of hyaluronan synthase 3 in deformed human temporomandibular joint discs: in vivo and in vitro studies.

The present study aimed at investigating the expression of a hyaluronan synthase (HAS) 3 in tissue samples of deformed human temporomandibular joint (TMJ) discs and cells obtained from the discs. Fifteen adult human TMJ discs (twelve diseased discs and three normal discs) were used in this study. The twelve diseased discs were obtained from twelve patients with internal derangement (ID) of TMJ. These patients all had anteriorly displaced discs and deformed discs. The tissues were immunohistochemically stained using HAS3 antibodies. In addition, the subcultured TMJ disc cells under both normal and hypoxic conditions (O2: 2%) were incubated for 3, 6, 12, and 24 h after addition of interleukin-1ß (IL-1ß) (1 ng/mL). Subsequently, the expression of HAS3 was examined using real-time reverse transcription-polymerase chain reaction (RT-PCR). The control group showed from negative to weak positive reactions for HAS3 on immunohistochemical staining. The discs extracted from twelve cases with ID presented from moderate to strong positive reactions for HAS3. The quantity of HAS3 mRNA was compared with a control group, and showed a 204-fold increase at 3 h, a 26-fold increase at 6 h, a 2.5-fold increase at 12 h and a 32-fold increase at 24 h under hypoxia with the addition of IL-1ß. The expression of HAS3 mRNA was significantly enhanced at 3 h and 24 h. The results obtained suggest that HAS3 is related to the pathological changes of human TMJ discs affected by ID.

Expression of lumican in the articular disc of the human temporomandibular joint.

Lumican belongs to the small leucine-rich repeat proteoglycan (SLRP) gene family and has been reported to exist in the cornea, intervertebral disc and tendon. Lumican plays a significant role in the assembly and regulation of collagen fibres. The human temporomandibular joint (TMJ) disc is made up of fibrocartilage with an extracellular matrix (ECM) composed of collagen and proteoglycans. The existence and behaviour of lumican has not been studied in the human TMJ disc. Therefore, we used immunohistochemical methods to detect lumican, CD34 and vascular endothelial growth factor (VEGF) and histochemical staining with toluidine blue in 13 human TMJ specimens (10 surgically removed and 3 obtained from autopsy). In both the normal and the deformed discs we observed staining with toluidine blue. We found that the area of metachromasia inside the deformed disc was uneven and expression of lumican was strong in the areas negative for metachromasia. Staining of VEGF and CD34 inside the deformed disc was seen. We confirmed the expression of lumican in the human TMJ disc and showed that a large number of fibroblast-like cells existed in the area of strong lumican expression. These new findings about the behaviour of lumican suggest that it may play a key role in the generation of a new collagen network by fibroblast-like cells.

Effect of hypoxia and interleukin-1beta on expression of tenascin-C in temporomandibular joint.

OBJECTIVE: The expression of tenascin-C in the synovial membrane of the internal derangement (ID) of the temporomandibular joint (TMJ) has been reported. Hypoxia of the synovial membrane in TMJ is considered to be a cause for the pathophysiology of ID. In this study, we clarify the contribution of hypoxia and interleukin-1beta in the expression of tenascin-C in ID of TMJ. MATERIALS AND METHODS: Synovial fibroblasts and disk cells obtained from ID of TMJs were cultured and treated with interleukin-1beta under normoxia and hypoxia. A Western blot analysis and reverse transcription-polymerase chain reaction analysis were used to identify tenascin-C in cultured synovial fibroblasts and disk cells. In addition, the immunohistochemical staining of tenascin-C was carried out for the specimens of ID of TMJs and normal. RESULTS: The combination of hypoxia and interleukin-1beta caused a significant increase in tenascin-C protein and mRNA of synovial fibroblasts. In contrast, the combination caused no increase in tenascin-C in disk cells. However, the immunohistochemical staining demonstrated tenascin-C to be significantly detected in both the synovial tissue and disks in ID of TMJ. CONCLUSIONS: These results indicate that hypoxic conditions with inflammation modulate the tenascin-C expression in synovial fibroblasts, but not in disk cells.

Operation with a single-channel thin-fibre arthroscope in patients with internal derangement of the temporomandibular joint.

We evaluated the use of operation by single-puncture arthroscopy in 55 patients (62 joints) with locked temporomandibular joints (TMJ). We used a single-channel thin-fibre arthroscope (M & M Co., Tokyo, Japan) and a holuminium yttrium aluminium garnet (Ho:YAG) laser (Lumenis Co., Tokyo, Japan). The preoperative mean (SD) maximum interincisal measurement (distance between the edge of the lower and upper incisor) was 26.0 (4.9) mm, and it was increased by 15.0mm 12 weeks after operation. The preoperative mean (SD) visual analogue score (VAS) was 6.3(2.0), and after 12 weeks it had been reduced to 1.6 (1.1). There were no other complaints. Single-puncture arthroscopy with the Ho:YAG laser is simple and useful. There were no other complications, and the results obtained were satisfactory.