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Necroptotic TNFα-Syndecan 4-TNFα Vicious Cycle as a Therapeutic Target for Preventing Temporomandibular Joint Osteoarthritis |
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| Authors: | Feng He Yuanjun Ma Shi Li Haozhe Ren Qian Liu Xiaohua Chen Hui Miao Tao Ye Qian Lu Zuge Yang Tianle Li Xin Tong Hongxu Yang Mian Zhang Helin Wang Yazhou Wang Shibin Yu |
| Institution: | 1. State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Oral Diseases, School of Stomatology, the Fourth Military Medical University, Xi'an, PR China;2. State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Oral Diseases, School of Stomatology, the Fourth Military Medical University, Xi'an, PR China
Contribution: Data curation, Formal analysis, ?Investigation, Software;3. Department of Stomatology, Seventh Medical Center of Chinese PLA General Hospital, Beijing, PR China Contribution: Formal analysis, ?Investigation, Software;4. Health Science Center, Xi'an Jiaotong University, Xi'an, PR China Contribution: ?Investigation, Writing - original draft;5. State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Oral Diseases, School of Stomatology, the Fourth Military Medical University, Xi'an, PR China Contribution: ?Investigation, Writing - original draft;6. State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Oral Diseases, School of Stomatology, the Fourth Military Medical University, Xi'an, PR China Contribution: ?Investigation;7. State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Oral Diseases, School of Stomatology, the Fourth Military Medical University, Xi'an, PR China Contribution: Funding acquisition, ?Investigation;8. State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Oral Diseases, Department of Central Sterile Supply, School of Stomatology, the Fourth Military Medical University, Xi'an, PR China Contribution: ?Investigation;9. State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Oral Diseases, School of Stomatology, the Fourth Military Medical University, Xi'an, PR China Contribution: ?Investigation, Software;10. State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Department of Medical Rehabilitation, School of Stomatology, the Fourth Military Medical University, Xi'an, PR China Contribution: Funding acquisition, ?Investigation;11. Department of Neurobiology, Institute of Neurosciences, School of Basic Medicine, the Fourth Military Medical University, Xi'an, PR China |
| Abstract: | Temporomandibular joint osteoarthritis (TMJOA) is a chronic degenerative disease for which the underlying mechanism still remains unclear. Compared with apoptosis and autophagy, necroptosis causes greater harm to tissue homeostasis by releasing damage-associated molecular patterns (DAMPs). However, the role of necroptosis and downstream key DAMPs in TMJOA is unknown. Here, rodent models of TMJOA were established by the unilateral anterior crossbite (UAC). Transmission electron microscopy (TEM) and immunohistochemistry of receptor interacting protein kinase 3 (RIPK3)/phosphorylation of mixed lineage kinase domain-like protein (pMLKL) were conducted to evaluate the occurrence of necroptosis in vivo. The therapeutic effects of blocking necroptosis were achieved by intra-articularly injecting RIPK3 or MLKL inhibitors and using RIPK3 or MLKL knockout mice. In vitro necroptosis of condylar chondrocyte was induced by combination of tumor necrosis factor alpha (TNFα), second mitochondria-derived activator of caspases (SMAC) mimetics and carbobenzoxy-valyl-alanyl-aspartyl-O-methyl]- fluoromethylketone (z-VAD-fmk). The possible DAMPs released by necroptotic chondrocytes were screened by quantitative proteomics and blocked by specific antibody. Translucent cytosol, swollen organelles, and ruptured cell membranes, features of necroptosis, were frequently manifested in chondrocytes at the early stage of condylar cartilage degeneration in TMJOA, which was accompanied by upregulation of RIPK3/pMLKL. Inhibiting or knocking out RIPK3/MLKL significantly prevented cartilage degeneration. DAMPs released by necroptotic condylar chondrocytes, such as syndecan 4 (SDC4) and heat shock protein 90 (HSP90), were verified. Furthermore, blocking the function of SDC4 significantly attenuated the expression of TNFα in cartilage and synovium, and accordingly increased cartilage thickness and reduced synovial inflammation. Thus, the necroptotic vicious cycle of TNFα-SDC4-TNFα contributes to cartilage degeneration and synovitis, and can serve as a potential therapeutic target for treating TMJOA. © 2022 American Society for Bone and Mineral Research (ASBMR). |
| Keywords: | TEMPOROMANDIBULAR OSTEOARTHRITIS CARTILAGE DEGENERATION NECROPTOSIS DAMAGE ASSOCIATED MOLECULAR PATTERNS SYNDECAN 4 |