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M1 macrophage polarization and synovitis play an important role in the pathogenesis of temporomandibular joint osteoarthritis (TMJOA). Reduced molecular weight of hyaluronic acid (HA) in synovial fluid of patients with TMJOA. In addition, high molecular weight hyaluronic acid (HMW-HA) is often used clinically to treat TMJ inflammation. As a pattern recognition receptor of the cytoplasm, ALPK1 was found to be pro-inflammatory in a variety of diseases. However, the relationship of ALPK1, HA and M1 macrophage polarization in TMJ synovitis remains unclear. We aimed to investigate the role of ALPK1 and HA in macrophage polarization and TMJ synovitis and the underlying mechanisms. The results demonstrated that ALPK1 was highly upregulated in the synovial macrophages in the inflamed TMJ synovium of patients. Low molecular weight hyaluronic acid (LMW-HA) promoted the expression of ALPK1 and M1 macrophage-associated genes. Besides, rhALPK1 promoted the expression of M1 macrophage-associated factors and the nuclear translocation of PKM2. Furthermore, ALPK1 knockout mice exhibited limited infiltration of macrophages and decreased expression levels of M1 macrophage-associated genes in CFA-induced TMJ synovitis. While HMW-HA inhibited the expression of ALPK1 and M1 macrophage polarization. Our results elucidated that ALPK1 promoted TMJ synovitis by promoting nuclear PKM2-mediated M1 macrophage polarization, whereas HMW-HA inhibited the expression of ALPK1 as well as M1 macrophage polarization., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Objectives: Innate immunity plays a significant role in the pathogenesis of temporomandibular joint osteoarthritis (TMJOA), which is characterized by synovial inflammation and condylar cartilage degradation. We are urged to investigate the impact of Resatorvid, a preventative drug that inhibits Toll-like receptor 4 (TLR4), on experimental inflammatory TMJOA pathology., Methods: An intra-articular injection of complete Freund's adjuvant (CFA) was used to induce an experimental inflammatory mouse TMJOA model, and TLR4 expression was identified by immunofluorescent labeling. Intraperitoneal injections of Resatorvid were administered to CFA-induced TMJOA mice, and the pathology of TMJOA animals with and without Resatorvid treatment was examined by H&E, Safranin-O/Fast Green, and TRAP staining, as well as micro-CT, immunohistochemistry, and immunofluorescence. The impact of Resatorvid on chondrocyte pyroptosis and macrophage inflammation was further investigated using ATDC5 chondrocytes and RAW264.7 macrophages pretreated with relevant antagonists., Results: CFA-induced TMJOA mice revealed remarkable synovial inflammation, together with a time course of cartilage degradation and bone destruction, with TLR4 elevated in the synovium and condylar cartilage. Prophylactic treatment with Resatorvid mitigated synovial inflammation, cartilage degeneration, and bone destruction in CFA-induced TMJOA mice and downregulated MyD88/NF-κB expression. Ex vivo studies demonstrated that Resatorvid treatment alleviated NOD-like receptor protein 3 (NLRP3)-mediated chondrocyte pyroptosis and degeneration and relieved macrophage inflammation by preventing reactive oxygen species (ROS) production through NLRP3 signaling., Conclusion: Prophylactic treatment with Resatorvid alleviates TMJOA pathology by inhibiting chondrocyte pyroptosis and degeneration, as well as ROS-induced macrophage inflammation, through TLR4/MyD88/NF-κB/NLRP3., (© 2023. The Author(s).)

Alpha-kinase 1 (ALPK1), a member of the alpha-kinase family, has been shown to be involved in mediating inflammatory responses and is strongly associated with gout; however, its modulatory role in osteoarthritis (OA) remains unclear. Here, we uncovered elevation of ALPK1 in degraded cartilage of destabilized medial meniscus (DMM) and collagenase-induced osteoarthritis (CIOA), two different mouse OA models induced by mechanical stress or synovitis. Intraarticular administration of recombinant human ALPK1 (rhALPK1) in vivo exacerbated OA pathogenesis in both DMM and CIOA mice, whereas ALPK1 knockout reversed this process. In vitro study demonstrated that ALPK1 aggravates metabolic disturbances in chondrocytes by enhancing the production of NOD-like receptor protein 3 (NLRP3), an inflammasome sensors driving interlukin-1β (IL-1β)-mediated inflammatory conditions. Furthermore, the selective inhibition of nuclear factor-κB (NF-κB) or NLRP3 indicates that NLRP3 is a downstream signaling governed by NF-κB in ALPK1-activated chondrocytes. Collectively, these results establish ALPK1 as a novel catabolic regulator of OA pathogenesis, and targeting this signaling may be a promising treatment strategy for OA. © 2022 American Society for Bone and Mineral Research (ASBMR)., (© 2022 American Society for Bone and Mineral Research (ASBMR).)

Background: High- mobility group 1 protein (HMGB1) is related with inflammation. Our former research reported that substantial HMGB1 situates at the synovium of osteoarthritis of temporomandibular joint (TMJOA) patients., Objective: This study investigated whether HMGB1 promotes synovial angiogenesis of TMJOA and its underlying mechanism., Methods: Human synovial fibroblasts were stimulated with HMGB1; the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible transcription factor-1α (HIF-1α) in these cells was explored by Western blotting, real-time PCR and immunofluorescent staining. The angiogenic capacity of these cells was assayed by tube formation and cell migration of human umbilical vein endothelial cells (HUVECs). The specific inhibitor against HMGB1, VEGF, Erk or JNK was added in these cells, respectively. Complete Freund's adjuvant (CFA)-induced TMJOA rats were produced. The changes in their synovium and synovial fluid were detected by immunofluorescent staining and ELISA., Results: HMGB1 effectively up-regulated the production of VEGF and HIF-1α in TMJOA synovial fibroblasts through the activation of Erk and JNK. Conditioned medium from HMGB1-treated TMJOA synovial fibroblasts significantly promoted tube formation and migration in HUVECs, while attenuated those after the addition of certain inhibitor for VEGF. Furthermore, the specific inhibitor against HMGB1 vanished the neovascularisation and production of HIF-1α, VEGF and CD34 in the synovium of rat TMJOA induced by CFA injection. Additionally, this inhibitor led to the reduction of IL-6, IL-1β and TNF-α in the synovial fluid of those rats., Conclusion: These findings disclose a key role for HMGB1 in governing synovial angiogenesis and as a therapeutic target against TMJOA., (© 2020 John Wiley & Sons Ltd.)

The abundance of inflammatory mediators in injured joint indicates innate immune reactions activated during temporomandibular joint osteoarthritis (TMJOA) progression. Toll-like receptor 4 (TLR4) can mediate innate immune reaction. Herein, we aimed to investigate the expression profile and effect of TLR4 in the cartilage and subchondral bone of the discectomy-induced TMJOA mice. The expression of TLR4 and NFκB p65 in the synovium of TMJOA patients was measured by immunohistochemistry, Western blotting and RT-PCR. H&E and Masson staining were utilized to assess the damage of cartilage and subchondral bone of the discectomy-induced TMJOA mice. A TLR4 inhibitor, TAK-242, was used to assess the effect of TLR4 in the cartilage and subchondral bone of the discectomy-induced TMJOA mice by Safranin O, micro-CT, immunofluorescence and immunohistochemistry. Western blotting was used to quantify the expression and effect of TLR4 in IL-1β-induced chondrocytes. The expression of TLR4 and NFκB p65 was elevated in the synovium of TMJOA patients, compared with the normal synovium. TLR4 elevated in the damaged cartilage and subchondral bone of discectomy-induced TMJOA mice, and the rate of TLR4 expressing chondrocytes positively correlated with OA score. Intraperitoneal injections of TAK-242 ameliorate the extent of TMJOA. Furthermore, TLR4 promotes the expression of MyD88/NFκB, pro-inflammatory and catabolic mediators in cartilage of discectomy-induced TMJOA. Besides, TLR4 participates in the production of MyD88/NFκB, pro-inflammatory and catabolic mediators in IL-1β-induced chondrocytes. TLR4 contributes to the damage of cartilage and subchondral bone in discectomy-induced TMJOA mice through activation of MyD88/NFκB and release of pro-inflammatory and catabolic mediators., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Osteoarthritis (OA) is a common joint degenerative disease that causes pain, joint damage, and dysfunction. External hyaluronic acid (HA) supplement is a common method for the management of osteoarthritis which requires multi-injections. It is demonstrated that biodegradable mesoporous silica nanoparticles successfully deliver an enzyme, hyaluronan synthase type 2 (HAS2), into synoviocytes from the temporomandibular joint (TMJ) and generate endogenous HA with high molecular weights. In a rat TMJ osteoarthritis inflammation model, this strategy promotes endogenous HA production and inhibits the synovial inflammation of OA for more than 3 weeks with one-shot administration. Such nanotherapy also helps repairing the bone defects in a rat OA bone defect model., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Temporomandibular joint (TMJ) osteoarthritis(OA)characterized with cartilage degen-eration is associated with inflammation. High mobility group box chromosomal protein-1(HMGB-1)is a potent mediator of inflammation and the trigger of OA. The expression of HMGB-1 in TMJ OA was uncovered, but the role of HMGB-1 in TMJ cartilage degeneration is not fully understood. In this study, the regulation of HMGB-1 in TMJ condylar cartilage was revealed., Methods: A complete Freund's adjuvant (CFA)-induced TMJ inflammation animal model was employed and the expression of HMGB-1 was detected at 1st, 2nd, and 6th weeks by immunohistochemistry. TMJ condylar chondrocytes were incubated with IL-1β (10 and 40 ng/ml) at 24, 48, and 72 h, and the translocation and protein level of HMGB-1 were evaluated by immunofluorescence and Western blot., Result: Nuclear HMGB-1 staining was predominantly located in chondrocytes of both the fibrosis and proliferative zones in healthy TMJ. 1st week and 2nd week after CFA injection, immunoreaction could be detected in the cytoplasms of HMGB-1-positive cells and cartilage matrix especially in hypertrophic zone. At 6th week after CFA injection, cartilage matrix expression was disappeared and the cytoplasm expression of HMGB-1 was very weak in hypertrophic zone. HMGB-1 was translocated from the nucleus to the cytoplasm at 48 h after incubated with IL-1β (10 ng/ml and 40 ng/ml). The protein level of HMGB-1 was increased after stimulation and had a peak at 48 h., Conclusion: HMGB-1 might be associated with TMJ inflammation and OA. Insight into the role of HMGB-1 in TMJ inflammation is helpful to add the new knowledge into the pathogenesis of TMJ OA., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: High-mobility group box protein-1 (HMGB-1), a potent promoter of inflammation, was believed to be a potential trigger of osteoarthritis (OA). Only a few studies have investigated the role of HMGB-1 in temporomandibular joint (TMJ) OA, especially in disc perforation cases. But in this study, not only the expression of HMGB-1 in TMJ OA with disc perforation was investigated but also the possible role of HMGB-1 in TMJ OA was discussed., Methods: Synovial membrane and disc specimens were collected from patients with TMJ OA, and the expression of HMGB-1 was detected using immunohistochemistry, real-time quantitative PCR and Western blotting., Results: High-mobility group box protein-1 expressed strongly in cytoplasm and nucleus of lining layer cells and endothelial cells in osteoarthritic synovium. Staining of HMGB-1 was found intensive in the frontier tissue of the perforation in the perforated discs. HMGB-1 expression was also upregulated in osteoarthritic synovial cells and disc cells according to real-time quantitative PCR and Western blotting analysis., Conclusions: High-mobility group box protein-1 expression was upregulated in TMJ OA and might promote the progression of TMJ OA., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Synovial inflammation and intra‐articular excessive pressure were accepted as two predominant etiologies for temporomandibular joint osteoarthritis (TMJOA). Toll‐like receptor 2 (TLR2) exerts roles both in certain inflammation‐ and pressure‐induced diseases. We aim to detect the role of TLR2 in the synovitis‐ or discectomy‐induced TMJOA mice. Materials and methods: Complete Freund's adjuvant (CFA)‐ and discectomy‐induced TMJOA mice were established, and pretreated with TLR2 inhibitor CU‐CPT22. Synovial inflammation, deterioration of cartilage and subchondral bone were measured by H&E and Safranin‐O staining, as well as micro‐CT. Western blotting was utilized to quantify TLR2's effect in inflammation‐ or pressure‐stimulated chondrocytes derived from rat TMJs. Results: Obvious synovitis occurred in CFA‐injection mice, while unapparent inflammatory change in discectomy mice. TLR2 elevated in cartilage and synovium of CFA‐injection mice, whereas no alterations in discectomy mice. TLR2 contributed to the synovitis, deterioration of cartilage and subchondral bone in CFA‐injection mice instead of discectomy mice. TLR2 induced the production of inflammatory and catabolic factors in rat chondrocytes by IL‐1β other than pressure. Conclusion: Toll‐like receptor 2 mediates synovitis, damage of cartilage and subchondral bone in CFA‐induced TMJOA model, but not discectomy‐induced TMJOA. TLR2 could be a potential target to prevent the deterioration of early phase TMJOA. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the role and mechanisms of programmed cell death 4 (PDCD4) in chondrocytes from temporomandibular joint osteoarthritis (TMJOA) rats. Material and Methods: Hematoxylin and eosin, Safranin O, and micro‐CT were used to detect the morphologic changes in condyles in rat TMJs receiving iodoacetic acid (MIA). The expression of PDCD4, and autophagy‐ and apoptosis‐related proteins in these condyles was measured by immunohistochemistry. Next, using a small interference RNA against PDCD4 (siPDCD4‐1086) and/or specific signaling activators, the alteration of PDCD4, and autophagy‐ and apoptosis‐related proteins, as well as Akt and JNK in the IL‐1β‐treated chondrocytes from rat TMJ, was detected by Western blot, immunofluorescence, and flow cytometry, respectively. Results: Elevation of PDCD4 and reduction in Beclin1, LC3II, and Bcl2 were observed in OA‐like lesions after MIA injection into rat TMJs. Then, PDCD4 downregulated autophagy and promoted apoptosis in the IL‐1β‐treated chondrocytes. Furthermore, Akt, not JNK, was responsible for PDCD4‐induced suppressed autophagy and enhanced apoptosis in the IL‐1β‐treated chondrocytes. Conclusion: PDCD4 is highly expressed in the rat cartilage of MIA‐induced TMJOA and IL‐1β‐treated primary chondrocytes. PDCD4 inhibits autophagy and promotes apoptosis via Akt in these cells. [ABSTRACT FROM AUTHOR]