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      Chrysin Attenuates the NLRP3 Inflammasome Cascade to Reduce Synovitis and Pain in KOA Rats

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          Abstract

          Purpose

          Our recent reports have revealed that inhibiting NLRP3 activation reduces synovial inflammation and fibrosis in knee osteoarthritis (KOA). Synovial inflammation is involved the entire process of KOA and promotes the progression of KOA. Natural flavonoid Chrysin from Scutellariae Radix, a traditional Chinese medicine, exhibits multifarious biological activities and potentially has protective activity against osteoarthritis. However, the mechanism of Chrysin in the treatment of synovial inflammation remains elusive. The purpose of our research was to explore the anti-inflammatory effects of Chrysin on KOA, which was induced by monoiodoacetic acid (MIA) in rats by targeting the NLRP3 inflammasome in the hopes of identifying an effective drug to treat KOA.

          Methods

          The MIA-induced KOA model was used to evaluate the cold pain threshold and paw withdrawal threshold (PWT) of joints after MIA (40 mg/mL) injection into the knee joints. Microscopically, we used LPS (5 ug/mL) and ATP (4 mmol/L) to stimulate fibroblast-like synovial cells (FLSs) to explore the underlying mechanisms and effects of Chrysin. Two staining methods, H&E and Sirius Red, were applied to assess histopathological changes in synovial membranes. Cellular signal transduction was determined by qRT-PCR and WB. Cytokine expression (inflammatory cytokines and pain-related cytokines) was detected by ELISA. The degree of chronic inflammatory pain was evaluated by c-Fos immunofluorescence.

          Results

          The results showed that Chrysin not only attenuated synovial inflammation but also reduced the secretion of pain-related factors and increased the PWT and cold pain threshold in rats. Chrysin also inhibited NLRP3 inflammasome activation and increased IL-1β levels to alleviate the synovitis.

          Conclusion

          Chrysin can relieve knee synovial inflammation and improve pain behavior in KOA rats, which may be related to the ability of Chrysin to inhibit NLRP3 inflammasome activation. Therefore, Chrysin may be developed as a new drug for the treatment of KOA.

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          Most cited references 36

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          The Role of Inflammatory and Anti-Inflammatory Cytokines in the Pathogenesis of Osteoarthritis

          Osteoarthritis (OA) is the most common chronic disease of human joints. The basis of pathologic changes involves all the tissues forming the joint; already, at an early stage, it has the nature of inflammation with varying degrees of severity. An analysis of the complex relationships indicates that the processes taking place inside the joint are not merely a set that (seemingly) only includes catabolic effects. Apart from them, anti-inflammatory anabolic processes also occur continually. These phenomena are driven by various mediators, of which the key role is attributed to the interactions within the cytokine network. The most important group controlling the disease seems to be inflammatory cytokines, including IL-1 β , TNF α , IL-6, IL-15, IL-17, and IL-18. The second group with antagonistic effect is formed by cytokines known as anti-inflammatory cytokines such as IL-4, IL-10, and IL-13. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of OA with respect to inter- and intracellular signaling pathways is still under investigation. This paper summarizes the current state of knowledge. The cytokine network in OA is put in the context of cells involved in this degenerative joint disease. The possibilities for further implementation of new therapeutic strategies in OA are also pointed.
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            Epidemiology of osteoarthritis

             Ernest Vina,  C Kwoh (2018)
            The purpose of this review is to highlight recent studies of osteoarthritis epidemiology, including research on prevalence, disease impact, and potential risk factors.
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              Synovitis in knee osteoarthritis: a precursor of disease?

              It is unknown whether joint inflammation precedes other articular tissue damage in osteoarthritis. Therefore, this study aims to determine if synovitis precedes the development of radiographic knee osteoarthritis (ROA).
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                28 July 2020
                2020
                : 14
                : 3015-3027
                Affiliations
                [1 ]Department of Orthopedics, The Affiliated Hospital of Nanjing University of Chinese Medicine , Nanjing, Jiangsu 210029, People’s Republic of China
                [2 ]Jiangsu Province Hospital of Chinese Medicine , Nanjing, Jiangsu 210029, People’s Republic of China
                [3 ]Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine , Nanjing, Jiangsu 210029, People’s Republic of China
                Author notes
                Correspondence: Peimin Wang Department of Orthopedics, The Affiliated Hospital of Nanjing University of Chinese Medicine , No. 155 Hanzhong Road, Qinhuai District, Nanjing, Jiangsu210029, People’s Republic of ChinaTel +86 15279703634 Email drwpm@163.com
                [*]

                These authors contributed equally to this work

                Article
                261216
                10.2147/DDDT.S261216
                7396814
                © 2020 Liao et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 5, Tables: 1, References: 44, Pages: 13
                Funding
                Funded by: National Natural Science Foundation of China, open-funder-registry 10.13039/501100001809;
                Funded by: the Leading Talents of Traditional Chinese Medicine Project;
                Funded by: Nanjing University of Chinese Medicine “Jiangsu University Nursing Advantage Discipline Construction Project Funding Project”;
                The current work was supported by the National Natural Science Foundation of China (No. 81774334), the Leading Talents of Traditional Chinese Medicine Project (SLJ0207) and Nanjing University of Chinese Medicine “Jiangsu University Nursing Advantage Discipline Construction Project Funding Project” (2019YSHL085).
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                koa, chrysin, synovitis, pain, nlrp3 inflammasome

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