The GSK‑3β/β‑catenin signaling pathway is involved in HMGB1‑induced chondrocyte apoptosis and cartilage matrix degradation

Shu, Zhiyong; Miao, Xiaogang; Tang, Tainhua; Zhan, Peng; Zeng, Langqing; Jiang, Yuchen

doi:10.3892/ijmm.2020.4460

Cited by 14 publications

(16 citation statements)

References 52 publications

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“…In this study, the levels of MMP-13, β-catenin gene, and protein in the cartilage of the model group were significantly increased; on the contrary, the expression of GSK-3β was significantly decreased, suggesting that high concentration of β-catenin can activate the Wnt/β-catenin pathway and promote the expression of MMP13, which leads to the degradation of cartilage matrix, and finally causes the degeneration of articular cartilage. The results are consistent with those of Shu et al [ 33 ]. Notably, after the addition of T-614, it reversed the expression of these factors in a dose-on-dose manner.…”

Section: Discussionsupporting

confidence: 94%

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: 94%

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

et al. 2021

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“…FLSs are important factors in KOA inflammation and joint destruction during the pathological progression of Koa, primarily by secreting a wide range of proinflammatory mediators, such as il-1β, il-18, TnF-α and MMPs (38). HMGB1 has been reported to serve a proinflammatory role in KOA (23,26), and HMGB1 levels in synovial fluid are closely associated with the severity of Koa (39). on the one hand, as an important proinflammatory factor in KOA, HMGB1 is responsible for promoting cartilage degradation and inducing synovitis by binding to raGe, Toll-like receptor 4 and other receptor (40).…”

Section: Discussionmentioning

confidence: 99%

“…HMGB1 has been reported to serve a proinflammatory role in KOA ( 23 , 26 ), and HMGB1 levels in synovial fluid are closely associated with the severity of KOA ( 39 ). On the one hand, as an important proinflammatory factor in KOA, HMGB1 is responsible for promoting cartilage degradation and inducing synovitis by binding to RAGE, Toll-like receptor 4 and other receptor ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

Relationship between the pyroptosis of fibroblast‑like synoviocytes and HMGB1 secretion in knee osteoarthritis

et al. 2020

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High mobility group box 1 (HMGB1) is an important downstream product of pyroptosis in macrophages, and it serves a vital role in numerous inflammatory diseases. Previous studies have reported that HMGB1 is released by fibroblast-like synoviocytes (FlSs) that are activated by inflammatory cytokines in knee osteoarthritis (Koa); however, the mechanism via which FlS promotes HMGB1 secretion in Koa remains unknown. according to our previous study, pyroptosis occurs in FlSs of patients with Koa and is mediated by nod-like receptor protein (nlrP)1 or nlrP3 inflammasomes. However, the specific relationship between HMGB1 secretion and FlS pyroptosis requires further investigation. in the present study, the association between HMGB1 secretion and FlS pyroptosis was investigated in vitro and in vivo. in this study, western blotting, eliSa and reverse transcription-quantitative Pcr were used to measure expression levels of proteins and mrna. caspase-1 activity assay and Hoechst 33342/Pi double staining were used to observe the pyroptosis of FlSs. Hematoxylin and eosin staining was used to observe the destruction of cartilage in Koa. increased expression levels of pyroptosis-related proteins and HMGB1 in the synovium of rat anterior cruciate ligament transection-induced KOA models were identified, and these changes were significantly mitigated via the intra-articular injection of a caspase-1 inhibitor. In vitro, FlSs were treated with lipopolysaccharide (lPS) + aTP to induce pyroptosis, and HMGB1 secretion was subsequently measured. LPS + ATP significantly increased the expression levels of pyroptosis-related proteins and HMGB1 in FlSs, and these effects were significantly mitigated by small interfering RNAs targeting nlrP1, nlrP3, apoptosis-associated speck-like protein with a caspase-recruitment domain or caspase-1. Therefore, the present results indicated that nlrP1/nlrP3 inflammasome-mediated and caspase-1-dependent FlS pyroptosis increased HMGB1 secretion in KOA. These findings may provide a therapeutic strategy to decrease synovial inflammatory responses during Koa progression.

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“…Canonical wnt/β-catenin pathway could induce several types of MMPs via modulation of the Axin, APC, and GSK3β protein complex after cardiac injury [ 109 ] [ 110 ]. The activation of the GSK3β/β-catenin pathway was ever reported to contribute to HMGB1-induced chondrocyte expression of matrix metalloproteinases (MMPs) [ 111 ]. The increased phosphorylated inactive GSK-3 has participated in the cytoplasmic accumulation and translocation of β-catenin into the nucleus, resulting in the expressions of downstream target genes [ 112 ].…”

Section: Gsk3β-mediated Inflammation In Heartmentioning

confidence: 99%

GSK3 modulation in acute lung injury, myocarditis and polycystic kidney disease-related aneurysm

Liu

Chiang

Kao

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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The GSK‑3β/β‑catenin signaling pathway is involved in HMGB1‑induced chondrocyte apoptosis and cartilage matrix degradation

Cited by 14 publications

References 52 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

Relationship between the pyroptosis of fibroblast‑like synoviocytes and HMGB1 secretion in knee osteoarthritis

GSK3 modulation in acute lung injury, myocarditis and polycystic kidney disease-related aneurysm

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