Casticin suppresses monoiodoacetic acid-induced knee osteoarthritis through inhibiting HIF-1α/NLRP3 inflammasome signaling

Li, Xiaochen; Mei, Wei; Huang, Zhengquan; Zhang, Li; Xu, Bo; Shi, Xianglin; Xiao, Yancheng; Ma, Zhenyuan; Liao, Taiyang; Zhang, Haosheng; Wang, Peimin

doi:10.1016/j.intimp.2020.106745

Cited by 52 publications

(33 citation statements)

References 20 publications

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“…Under TEM, the chondrocyte microvilli were obviously recovered, the shedding particles and vacuole-like structure were significantly reduced, and the collagen fiber layer was tightly arranged. The above pathological changes were consistent with previous studies [ 18 , 22 ]. Taken together, our data suggested that T-614 may alleviate KOA progression by improving articular cartilage structure.…”

Section: Discussionsupporting

confidence: 93%

T-614 attenuates knee osteoarthritis via regulating Wnt/β-catenin signaling pathway

et al. 2021

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Background The aim of this study was to investigate the effect of Iguratimod (T-614) on rat knee osteoarthritis (KOA) and further to explore its underlying mechanism. Methods In this study, papain-induced KOA model was constructed. Hematoxylin and eosin (H&E) staining was conducted to observe the pathological changes of cartilage tissue and Mankin scoring principle was used for quantitative scoring. Transmission electron microscopy (TEM) was applied to observe the ultrastructure of cartilage tissue. ELISA was used to measure the levels of matrix metalloproteinase 13 (MMP-13) and inflammatory factors (interleukin (IL)-6 and tumor necrosis factor a (TNF-a)) in serum. RT-qPCR and immunohistochemistry were conducted to detect mRNA expression and protein expression of key genes in Wnt/β-catenin pathway. Results H&E, Mankin scoring, and TEM data confirmed that compared with model group, T-614 significantly improved the degeneration of articular cartilage. Besides, we observed that low, middle, and high doses of T-614 could decrease the levels of MMP13, TNF-α, and IL-6 in serum to different degrees. Mechanically, T-614 downregulated the mRNA and protein expression of β-catenin and MMP13 in cartilage tissue via a dose-dependent manner, and on the contrary upregulated the mRNA and protein expression of glucogen synthase kinase-3 beta (GSK-3β). Conclusion Our results suggested that T-614 can reduce the level of its downstream target gene MMP-13 and downregulate the expression of inflammatory cytokines TNF-α and IL-6 by regulating the Wnt/β-catenin signaling pathway, thereby inhibiting joint inflammation and controlling KOA degeneration of articular cartilage.

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Section: Discussionsupporting

confidence: 93%

T-614 attenuates knee osteoarthritis via regulating Wnt/β-catenin signaling pathway

et al. 2021

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“…The KOA and KOA + VA rats were injected with monosodium iodoacetate (MIA) in the knee to induced KOA ( Rannou et al, 2016 ). Our previous data showed that the knee joint diameter was significantly larger than the control at the 14th day ( Li et al, 2020 ). Therefore, from day 14, the KOA + VA group was given VA at 30 mg/kg (dissolved in 0.9% saline) every day via gastric intubation.…”

Section: Methodsmentioning

confidence: 90%

“…After dissociation, fibroblasts were collected via centrifugation at 1,500 rpm for 4 min and cultured in DMEM supplemented with 10% fetal calf serum (FCS; Gibco, Thermo Fisher Scientific, Waltham, MA, USA) and antibiotics (100 U/ml penicillin, 100 μg/ml streptomycin; Invitrogen, CA, USA). Cells were identified as described in our previous studies ( Li et al, 2020 ). Passages three to six of the synovial fibroblasts were used for the experiments.…”

Section: Methodsmentioning

confidence: 99%

Vanillic Acid Reduces Pain-Related Behavior in Knee Osteoarthritis Rats Through the Inhibition of NLRP3 Inflammasome-Related Synovitis

Huang

Zhang

et al. 2021

Front. Pharmacol.

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Objectives: Synovitis plays an important role in knee osteoarthritis (KOA) pain. The activation of the NOD-like receptor protein 3 (NLRP3) inflammasome in fibroblast-like synoviocytes (FLSs) promotes KOA development. In this study, we aimed to investigate whether vanillic acid (VA), a monomer derived from Chinese herbal medicines, could target NLRP3 inflammasome-related synovitis to reduce pain.Methods: Rats in the KOA and KOA + VA groups were injected with monosodium iodoacetate (MIA) in the knee to induce KOA. From day 14, the KOA + VA group was given VA at 30 mg/kg every day via gastric intubation. FLSs were collected from the synovial tissues. We examined both the protein and gene expression of caspase-1, apoptosis-associated speck-like protein with a caspase recruitment domain (ASC), NLRP3, components of the NLRP3 inflammasome, and interleukin-1β (IL-1β) and IL-18 in vivo and in vitro.Results: The upregulation of caspase-1, ASC, and NLRP3 in the KOA model were reduced by VA. VA also lowered the level of IL-1β and IL-18 in the KOA model. In addition, VA relieved pain-related behavior of KOA model rats and downregulated the pain mediators CGRP, NGF, and TrkA in FLSs. Interestingly, we also observed reduced synovial fibrosis in the animal experiments.Conclusion: Our research showed that VA reduces synovitis and pain-related behaviors in a rat model of KOA, which provides the basis for further investigations into the potential therapeutic impact of VA in KOA.

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“…Mediators of Inflammation 1α and type I collagen in synovial tissue. We followed the methods of Peimin Wang et al [22]. Briefly, sections were incubated in antigen retrieval buffer to unmask the antigen after a standard deparaffinization and rehydration process.…”

Section: Methodsmentioning

confidence: 99%

Agnuside Alleviates Synovitis and Fibrosis in Knee Osteoarthritis through the Inhibition of HIF-1α and NLRP3 Inflammasome

Zhang

et al. 2021

Mediators of Inflammation

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Increasing evidence has shown that NLRP3 inflammasome activation participates in chronic aseptic inflammation and is related to tissue fibrosis. Our last study also revealed the vital role of NLRP3 inflammasome, highly associated with tissue hypoxia, in the onset and development of knee osteoarthritis (KOA). In this study, we tried to find a possible benign intervention for that pathological process. Agnuside (AGN), a nontoxic, natural small molecule isolated from the extract of Vitex negundo L. (Verbenaceae), has been demonstrated to have antioxidation, anti-inflammatory, analgesia, and many other properties as an iridoid glycoside, although its specific target is still unclear. Therefore, we established MIA-induced KOA model rats and investigated the effects of AGN oral gavage on oxygen-containing state, NLRP3 inflammasome, synovitis, and fibrosis in KOA. Pimonidazole staining and HIF-1α immunohistochemical assay both showed that AGN at the oral dose of 6.25 mg/kg can effectively relieve local hypoxia in synovial tissue. Besides, we observed a decrease of HIF-1α, caspase-1, ASC, and NLRP3 after AGN intervention, both in the mRNA and protein levels. In addition, rats treated with the AGN showed less inflammatory reaction and fibrosis, not only in the expression of NLRP3, inflammasome downstream factors IL-1β and IL-18, and fibrosis markers TGF-β, TIMP1, and VEGF but also in the observation of HE staining, anatomical characteristics, Sirius Red staining, and type I collagen immunohistochemistry. Subsequently, we established LPS-induced models of fibroblast-like synoviocytes (FLSs) mimicking the inflammatory environment of KOA and activating NLRP3 inflammasome. FLSs treated with AGN (3 μM) resulted in a downregulation of HIF-1α and the components required for NLRP3 inflammasome activation. Meanwhile, the content of proinflammatory factors IL-1β and IL-18 in FLS supernatant was also reduced by AGN. In addition, both mRNA and protein levels of the fibrotic markers were significantly decreased after AGN management. To conclude, this study demonstrates that AGN alleviates synovitis and fibrosis in experimental KOA through the inhibition of HIF-1α accumulation and NLRP3 inflammasome activation. Additionally, not only does it reveal some novel targets for anti-inflammatory and antioxidant effects of AGN but also announces its potential value in treating KOA in humans.

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Casticin suppresses monoiodoacetic acid-induced knee osteoarthritis through inhibiting HIF-1α/NLRP3 inflammasome signaling

Cited by 52 publications

References 20 publications

T-614 attenuates knee osteoarthritis via regulating Wnt/β-catenin signaling pathway

T-614 attenuates knee osteoarthritis via regulating Wnt/β-catenin signaling pathway

Vanillic Acid Reduces Pain-Related Behavior in Knee Osteoarthritis Rats Through the Inhibition of NLRP3 Inflammasome-Related Synovitis

Agnuside Alleviates Synovitis and Fibrosis in Knee Osteoarthritis through the Inhibition of HIF-1α and NLRP3 Inflammasome

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