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

Abstract 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 o...

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Main Authors: Shan Cong, Yan Meng, Lingrui Wang, Jiao Sun, Ta bu shi·Nu er xia ti, Li Luo
Format: Article
Language:English
Published: BMC 2021-06-01
Series:Journal of Orthopaedic Surgery and Research
Subjects:
Online Access:https://doi.org/10.1186/s13018-021-02530-2
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author Shan Cong
Yan Meng
Lingrui Wang
Jiao Sun
Ta bu shi·Nu er xia ti
Li Luo
author_facet Shan Cong
Yan Meng
Lingrui Wang
Jiao Sun
Ta bu shi·Nu er xia ti
Li Luo
author_sort Shan Cong
collection DOAJ
description Abstract 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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spelling doaj.art-43338fa5f51e4198b3cd3e2e08f74eb02022-12-22T04:09:08ZengBMCJournal of Orthopaedic Surgery and Research1749-799X2021-06-0116111010.1186/s13018-021-02530-2T-614 attenuates knee osteoarthritis via regulating Wnt/β-catenin signaling pathwayShan Cong0Yan Meng1Lingrui Wang2Jiao Sun3Ta bu shi·Nu er xia ti4Li Luo5Department of Rheumatism and Immunology, First Affiliated Hospital of Xinjiang Medical UniversityDepartment of Rheumatism and Immunology, First Affiliated Hospital of Xinjiang Medical UniversityDepartment of Rheumatism and Immunology, Xinjiang Medical UniversityDepartment of Rheumatism and Immunology, First Affiliated Hospital of Xinjiang Medical UniversityDepartment of Rheumatism and Immunology, The Second Affiliated Hospital of Xinjiang Medical UniversityDepartment of Rheumatism and Immunology, First Affiliated Hospital of Xinjiang Medical UniversityAbstract 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.https://doi.org/10.1186/s13018-021-02530-2Knee osteoarthritisArticular cartilageIguratimodInflammationWnt/β-catenin signaling pathway
spellingShingle Shan Cong
Yan Meng
Lingrui Wang
Jiao Sun
Ta bu shi·Nu er xia ti
Li Luo
T-614 attenuates knee osteoarthritis via regulating Wnt/β-catenin signaling pathway
Journal of Orthopaedic Surgery and Research
Knee osteoarthritis
Articular cartilage
Iguratimod
Inflammation
Wnt/β-catenin signaling pathway
title T-614 attenuates knee osteoarthritis via regulating Wnt/β-catenin signaling pathway
title_full T-614 attenuates knee osteoarthritis via regulating Wnt/β-catenin signaling pathway
title_fullStr T-614 attenuates knee osteoarthritis via regulating Wnt/β-catenin signaling pathway
title_full_unstemmed T-614 attenuates knee osteoarthritis via regulating Wnt/β-catenin signaling pathway
title_short T-614 attenuates knee osteoarthritis via regulating Wnt/β-catenin signaling pathway
title_sort t 614 attenuates knee osteoarthritis via regulating wnt β catenin signaling pathway
topic Knee osteoarthritis
Articular cartilage
Iguratimod
Inflammation
Wnt/β-catenin signaling pathway
url https://doi.org/10.1186/s13018-021-02530-2
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