Resatorvid Alleviates Experimental Inflammatory TMJOA by Restraining Chondrocyte Pyroptosis and Synovial Inflammation

Overview

Journal Arthritis Res Ther

Publisher Biomed Central

Specialty Rheumatology

Date 2023 Nov 29

PMID 38031141

Authors

Xin Liu

Huimin Li

Yaping Feng

Huilin Guo

Yingjie Li

Jin Ke

Xing Long

Affiliations

Soon will be listed here.

Abstract

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.

References

Bai H, Zhang Z, Liu L, Wang X, Song X, Gao L . Activation of adenosine A3 receptor attenuates progression of osteoarthritis through inhibiting the NLRP3/caspase-1/GSDMD induced signalling. J Cell Mol Med. 2022; 26(15):4230-4243. PMC: 9344816. DOI: 10.1111/jcmm.17438. View

Liu X, Zhao J, Jiang H, Guo H, Li Y, Li H . ALPK1 Accelerates the Pathogenesis of Osteoarthritis by Activating NLRP3 Signaling. J Bone Miner Res. 2022; 37(10):1973-1985. DOI: 10.1002/jbmr.4669. View

Gomez R, Villalvilla A, Largo R, Gualillo O, Herrero-Beaumont G . TLR4 signalling in osteoarthritis--finding targets for candidate DMOADs. Nat Rev Rheumatol. 2014; 11(3):159-70. DOI: 10.1038/nrrheum.2014.209. View

Nunes P, Mattioli S, Sandrim V . NLRP3 Activation and Its Relationship to Endothelial Dysfunction and Oxidative Stress: Implications for Preeclampsia and Pharmacological Interventions. Cells. 2021; 10(11). PMC: 8616099. DOI: 10.3390/cells10112828. View

Zhai Z, Yang F, Xu W, Han J, Luo G, Li Y . Attenuation of Rheumatoid Arthritis Through the Inhibition of Tumor Necrosis Factor-Induced Caspase 3/Gasdermin E-Mediated Pyroptosis. Arthritis Rheumatol. 2021; 74(3):427-440. PMC: 9305212. DOI: 10.1002/art.41963. View

Sanchez-Lopez E, Coras R, Torres A, Lane N, Guma M . Synovial inflammation in osteoarthritis progression. Nat Rev Rheumatol. 2022; 18(5):258-275. PMC: 9050956. DOI: 10.1038/s41584-022-00749-9. View

Lai Y, Zheng W, Qu M, Xiao C, Chen S, Yao Q . Kindlin-2 loss in condylar chondrocytes causes spontaneous osteoarthritic lesions in the temporomandibular joint in mice. Int J Oral Sci. 2022; 14(1):33. PMC: 9253313. DOI: 10.1038/s41368-022-00185-1. View

Feng S, Lei J, Chen H, Wang Y, Yap A, Fu K . Increased chemokine RANTES in synovial fluid and its role in early-stage degenerative temporomandibular joint disease. J Oral Rehabil. 2020; 47(9):1150-1160. DOI: 10.1111/joor.13041. View

Pantoja L, de Toledo I, Pupo Y, Porporatti A, De Luca Canto G, Zwir L . Prevalence of degenerative joint disease of the temporomandibular joint: a systematic review. Clin Oral Investig. 2018; 23(5):2475-2488. DOI: 10.1007/s00784-018-2664-y. View

10.

Albano G, Gagliardo R, Montalbano A, Profita M . Overview of the Mechanisms of Oxidative Stress: Impact in Inflammation of the Airway Diseases. Antioxidants (Basel). 2022; 11(11). PMC: 9687037. DOI: 10.3390/antiox11112237. View

11.

Bahrami A, Parsamanesh N, Atkin S, Banach M, Sahebkar A . Effect of statins on toll-like receptors: a new insight to pleiotropic effects. Pharmacol Res. 2018; 135:230-238. DOI: 10.1016/j.phrs.2018.08.014. View

12.

Pan Y, Cai W, Huang J, Cheng A, Wang M, Yin Z . Pyroptosis in development, inflammation and disease. Front Immunol. 2022; 13:991044. PMC: 9522910. DOI: 10.3389/fimmu.2022.991044. View

13.

Xu L, Polur I, Lim C, Servais J, Dobeck J, Li Y . Early-onset osteoarthritis of mouse temporomandibular joint induced by partial discectomy. Osteoarthritis Cartilage. 2009; 17(7):917-22. PMC: 2941347. DOI: 10.1016/j.joca.2009.01.002. View

14.

Peng S, Yan Y, Li R, Dai H, Xu J . Extracellular vesicles from M1-polarized macrophages promote inflammation in the temporomandibular joint via miR-1246 activation of the Wnt/β-catenin pathway. Ann N Y Acad Sci. 2021; 1503(1):48-59. DOI: 10.1111/nyas.14590. View

15.

Lu H, Xu X, Fu D, Gu Y, Fan R, Yi H . Butyrate-producing Eubacterium rectale suppresses lymphomagenesis by alleviating the TNF-induced TLR4/MyD88/NF-κB axis. Cell Host Microbe. 2022; 30(8):1139-1150.e7. DOI: 10.1016/j.chom.2022.07.003. View

16.

Motta F, Barone E, Sica A, Selmi C . Inflammaging and Osteoarthritis. Clin Rev Allergy Immunol. 2022; 64(2):222-238. DOI: 10.1007/s12016-022-08941-1. View

17.

Ma H, Shu Q, Li Z, Song X, Xu H . Formaldehyde aggravates allergic contact dermatitis by facilitating NLRP3 inflammasome activation in macrophages. Int Immunopharmacol. 2023; 117:109904. DOI: 10.1016/j.intimp.2023.109904. View

18.

Jiang H, Zhang Y, Hu G, Shang X, Ming J, Deng M . Innate/Inflammatory Bioregulation of Surfactant Protein D Alleviates Rat Osteoarthritis by Inhibiting Toll-Like Receptor 4 Signaling. Front Immunol. 2022; 13:913901. PMC: 9294227. DOI: 10.3389/fimmu.2022.913901. View

19.

Luo P, Zhao T, He H . IL-38-mediated NLRP3/caspase-1 inhibition is a disease-modifying treatment for TMJ inflammation. Ann N Y Acad Sci. 2021; 1508(1):92-104. DOI: 10.1111/nyas.14704. View

20.

Coll R, Schroder K, Pelegrin P . NLRP3 and pyroptosis blockers for treating inflammatory diseases. Trends Pharmacol Sci. 2022; 43(8):653-668. DOI: 10.1016/j.tips.2022.04.003. View