Yohimbine Ameliorates Temporomandibular Joint Chondrocyte Inflammation with Suppression of NF-κB Pathway.

Local joint inflammation plays an important role in the pathogenesis of temporomandibular joint (TMJ) osteoarthrosis (TMJOA). Yohimbine, an alpha-2 adrenergic receptor antagonist, possesses anti-inflammatory properties; however, the ability of Yohimbine to protect against TMJOA-associated chondrocyte inflammation remains unclear. We conducted in vitro and in vivo analyses to investigate whether Yohimbine could ameliorate TMJOA-induced chondrocyte inflammation and to elucidate the mechanisms involved. Chondrocytes of TMJOA mice were stimulated with interleukin (IL)-1ß or noradrenaline (NE), and the resulting production of inflammation-related factors was evaluated in the presence or absence of Yohimbine. Furthermore, two TMJOA mouse models were treated with Yohimbine and the therapeutic effect was quantified. NE (10-6 M) triggered inflammatory cytokine secretion by TMJ chondrocytes, and Yohimbine suppressed IL-1ß- or NE-induced IL-6 upregulation in TMJ chondrocytes with the nuclear factor (NF)-κB pathway inhibition. Yohimbine also ameliorated cartilage destruction in the TMJOA models. Interestingly, αmpT, a tyrosine hydroxylase inhibitor, reversed the effects of Yohimbine by activating the NF-κB pathway. Collectively, these findings show that Yohimbine ameliorated TMJ chondrocyte inflammation and the suppression of NF-κB pathway contributes to this effect.

Suberoylanilide Hydroxamic Acid Attenuates Interleukin-1ß-Induced Interleukin-6 Upregulation by Inhibiting the Microtubule Affinity-Regulating Kinase 4/Nuclear Factor-κB Pathway in Synovium-Derived Mesenchymal Stem Cells from the Temporomandibular Joint.

Synovium-derived mesenchymal stem cells (SMSCs) can migrate to the site of destroyed condylar cartilage and differentiate into chondrocytes to repair temporomandibular joint (TMJ) damage. Interleukin (IL)-1ß-induced IL-6 secretion has been shown to inhibit the chondrogenic potential of SMSCs. The histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) has recently been shown to be closely related to the inflammation induced by IL-1ß. However, the relationship between SAHA and IL-6 secretion induced by IL-1ß in SMSCs remains unclear. In this study, we evaluated the relationships between IL-1ß and IL-6 in synovial specimens from patients with TMD and in model rats with osteoarthritis (OA). We found that IL-1ß and IL-6 were positively correlated and that IL-6 expression in SMSCs increased with IL-1ß stimulation in vitro. Moreover, microtubule affinity-regulating kinase 4 (MARK4) was significantly upregulated in IL-1ß-stimulated SMSCs and in the synovium of rats with OA. MARK4 knockdown inhibited IL-6 secretion and nuclear factor (NF)-κB pathway activation in IL-1ß-stimulated SMSCs. SAHA attenuated IL-6 secretion in IL-1ß-induced SMSCs through NF-κB pathway inhibition, and MARK4 was also downregulated in SAHA-treated SMSCs. However, inhibition of the NF-κB pathway did not suppress MARK4 expression. Thus, these results showed that SAHA attenuated IL-6 secretion in IL-1ß-induced SMSCs through inhibition of the MARK4/NF-κB pathway.

Temporomandibular joint disorders contribute to anxiety in BalB/C mice.

Despite a high comorbidity between these two disorders, the physiological association between temporomandibular joint disorders (TMDs) and anxiety remains unknown. This study aimed to investigate whether TMDs contribute to anxiety through the induction of oligodendrogenesis in the hippocampus using a mouse model of TMD. Forty 8-week-old male BalB/C mice were used in the experiments. The mice were randomly divided into 4 groups: (1) control group (N group); (2) elevated occlusion group (E group); (3) restriction group (R group); and (4) elevated occlusion and restriction group (ER group). The mice were subjected to behavior tests of open field tests and elevated plus maze analysis. The serum corticosterone levels and expression of mature oligodendrocyte marker MBP and the oligodendrocyte marker RIP were analyzed. All data were statistically analyzed using by one-way analysis of variance. The TMD group showed condylar degeneration compared with the control group. Additionally, exposure to chronic restraint stress for 3 weeks after TMD significantly exacerbated anxiety-like behavior and resulted in a significant increase in serum corticosterone levels and in the expression of MBP and RIP in the dentate gyrus (DG) and CA3 in the hippocampus. Taken together, these data suggest that TMD lead to increased oligodendrogenesis in the hippocampus, which contributes to the development of anxiety-like behavior. TMD could contribute to anxiety by inducing oligodendrogenesis in the hippocampus.

HDAC10 upregulation contributes to interleukin 1ß-mediated inflammatory activation of synovium-derived mesenchymal stem cells in temporomandibular joint.

Histone deacetylases (HDACs) are important in chronic inflammation, and inflammatory responses affect synovium-derived mesenchymal stem cell (SMSC) function in temporomandibular joint repair. However, the effect of HDACs on SMSC inflammatory activation remains unclear. In this study, temporomandibular joint fibroblast-like synoviocytes obtained from osteoarthritis patients met the minimal mesenchymal stem cell criteria. Interleukin 1ß (IL-1ß) upregulated IL-6 and IL-8 expression in SMSCs through nuclear factor-κB (NF-κB) pathway activation. IL-6 and IL-8 upregulation were blocked by broad-acting HDAC inhibitors SAHA and LBH589. MC1568 alleviated IL-1ß activation of SMSCs, whereas CI994 and FK228 produced a minimal or opposite effect in vitro. We also found HDAC10 was highly associated with localized IL-1ß expression in vivo and in vitro. HDAC10 knockdown alleviated IL-1ß-mediated SMSC activation and blocked NF-κB pathway activation. Conversely, HDAC10 overexpression promoted IL-6 and IL-8 expression and IL-1ß-mediated NF-κB pathway activation. In conclusion, HDAC10 upregulation contributed to IL-1ß-mediated inflammatory activation of SMSCs, indicating that HDAC10 may be a novel therapeutic target.

The LncRNA ZBED3-AS1 induces chondrogenesis of human synovial fluid mesenchymal stem cells.

Human synovial fluid-derived mesenchymal stem cells (SFMSCs) have great potential for cartilage induction and are promising for cell-based strategies for articular cartilage repair. Many long non-coding RNAs (lncRNAs) regulate chondrogenesis of MSCs. We hypothesized that the divergent lncRNA ZBED3-AS1, which binds locally to chromatin, could promote the expression of zbed3, a novel Axin-interacting protein that activates Wnt/ß-catenin signaling, involved in chondrogenesis. However, the function of ZBED3-AS1 in SFMSCs is unclear. In this study, the expression, biological function, and roles of ZBED3-AS1 in SFMSC chondrogenesis were examined by multilineage differentiation, flow cytometry, and gain-of-function studies. We found that ZBED3-AS1 promotes chondrogenesis. Furthermore, ZBED3-AS1 could directly increase zbed3 expression. Finally, the wnt-inhibitor DKK1 could reverse the stimulatory effect of ZBED3-AS1 on chondrogenesis. These findings demonstrate the role of a new lncRNA, ZBED3-AS1, in SFMSC chondrogenesis and may improve osteoarthritis treatment.