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Silymarin modulates catabolic cytokine expression through Sirt1 and SOX9 in human articular chondrocytes

BACKGROUND: Silymarin (SMN), a polyphenolic flavonoid, is involved in multiple bioactive functions including anti-inflammation. Pretreatment with SMN demonstrated chondroprotection against tumour necrosis factor-alpha (TNF-α) stimulation in a chondrocyte cell line. However, pre- and posttreatment wi...

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Autores principales: Wu, Wen-Tien, Chen, Yi-Ru, Lu, Dai-Hua, Senatov, Fedor Svyatoslavovich, Yang, Kai-Chiang, Wang, Chen-Chie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896383/
https://www.ncbi.nlm.nih.gov/pubmed/33610183
http://dx.doi.org/10.1186/s13018-021-02305-9
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author Wu, Wen-Tien
Chen, Yi-Ru
Lu, Dai-Hua
Senatov, Fedor Svyatoslavovich
Yang, Kai-Chiang
Wang, Chen-Chie
author_facet Wu, Wen-Tien
Chen, Yi-Ru
Lu, Dai-Hua
Senatov, Fedor Svyatoslavovich
Yang, Kai-Chiang
Wang, Chen-Chie
author_sort Wu, Wen-Tien
collection PubMed
description BACKGROUND: Silymarin (SMN), a polyphenolic flavonoid, is involved in multiple bioactive functions including anti-inflammation. Pretreatment with SMN demonstrated chondroprotection against tumour necrosis factor-alpha (TNF-α) stimulation in a chondrocyte cell line. However, pre- and posttreatment with phytochemicals have varying effects on osteoarthritis (OA) chondrocytes, and the therapeutic potential of SMN after catabolic cytokine stimulation is not fully elucidated. METHODS: The cytotoxicity of SMN (12.5, 25, 50 and 100 μM) was evaluated in human primary chondrocytes. The chondrocytes were supplemented with SMN (25 and 50 μM) after interleukin-1beta (IL-1β) stimulation. The mRNA expression and protein production of catabolic/anabolic cytokines as well as extracellular matrix (ECM) components were evaluated. RESULTS: High-dose SMN (100 μM) impaired the mitochondrial activity in chondrocytes, and 50 μM SMN further caused cell death in IL-1β-stimulated cells. The addition of 25 μM SMN ameliorated cell senescence; downregulated the catabolic genes of inducible nitric oxide synthase, IL-1β, TNF-α, matrix metalloproteinase-3 (MMP-3), MMP-9 and MMP-13; upregulated the anabolic genes of tissue inhibitor of metalloproteinase-1 (TIMP-1) and collagen type II alpha 1; and restored the expression of chondrogenic phenotype genes SOX9 and sirtuin-1 (Sirt1). In addition, the production of IL-1β, MMP-3 and MMP-9 decreased with an increase in TIMP-1 secretion. However, the mRNA levels of IL-6, IL-8 and IL-10 and protein production remained high. The addition of nicotinamide, a Sirt1 inhibitor, downregulated SOX9 and attenuated the therapeutic effects of SMN on IL-1β-stimulated chondrocytes. CONCLUSION: SMN regulates the chondrocyte phenotype through Sirt1 and SOX9 to improve ECM homeostasis and may serve as a complementary therapy for early-stage knee OA.
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spelling pubmed-78963832021-02-22 Silymarin modulates catabolic cytokine expression through Sirt1 and SOX9 in human articular chondrocytes Wu, Wen-Tien Chen, Yi-Ru Lu, Dai-Hua Senatov, Fedor Svyatoslavovich Yang, Kai-Chiang Wang, Chen-Chie J Orthop Surg Res Research Article BACKGROUND: Silymarin (SMN), a polyphenolic flavonoid, is involved in multiple bioactive functions including anti-inflammation. Pretreatment with SMN demonstrated chondroprotection against tumour necrosis factor-alpha (TNF-α) stimulation in a chondrocyte cell line. However, pre- and posttreatment with phytochemicals have varying effects on osteoarthritis (OA) chondrocytes, and the therapeutic potential of SMN after catabolic cytokine stimulation is not fully elucidated. METHODS: The cytotoxicity of SMN (12.5, 25, 50 and 100 μM) was evaluated in human primary chondrocytes. The chondrocytes were supplemented with SMN (25 and 50 μM) after interleukin-1beta (IL-1β) stimulation. The mRNA expression and protein production of catabolic/anabolic cytokines as well as extracellular matrix (ECM) components were evaluated. RESULTS: High-dose SMN (100 μM) impaired the mitochondrial activity in chondrocytes, and 50 μM SMN further caused cell death in IL-1β-stimulated cells. The addition of 25 μM SMN ameliorated cell senescence; downregulated the catabolic genes of inducible nitric oxide synthase, IL-1β, TNF-α, matrix metalloproteinase-3 (MMP-3), MMP-9 and MMP-13; upregulated the anabolic genes of tissue inhibitor of metalloproteinase-1 (TIMP-1) and collagen type II alpha 1; and restored the expression of chondrogenic phenotype genes SOX9 and sirtuin-1 (Sirt1). In addition, the production of IL-1β, MMP-3 and MMP-9 decreased with an increase in TIMP-1 secretion. However, the mRNA levels of IL-6, IL-8 and IL-10 and protein production remained high. The addition of nicotinamide, a Sirt1 inhibitor, downregulated SOX9 and attenuated the therapeutic effects of SMN on IL-1β-stimulated chondrocytes. CONCLUSION: SMN regulates the chondrocyte phenotype through Sirt1 and SOX9 to improve ECM homeostasis and may serve as a complementary therapy for early-stage knee OA. BioMed Central 2021-02-20 /pmc/articles/PMC7896383/ /pubmed/33610183 http://dx.doi.org/10.1186/s13018-021-02305-9 Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Wu, Wen-Tien
Chen, Yi-Ru
Lu, Dai-Hua
Senatov, Fedor Svyatoslavovich
Yang, Kai-Chiang
Wang, Chen-Chie
Silymarin modulates catabolic cytokine expression through Sirt1 and SOX9 in human articular chondrocytes
title Silymarin modulates catabolic cytokine expression through Sirt1 and SOX9 in human articular chondrocytes
title_full Silymarin modulates catabolic cytokine expression through Sirt1 and SOX9 in human articular chondrocytes
title_fullStr Silymarin modulates catabolic cytokine expression through Sirt1 and SOX9 in human articular chondrocytes
title_full_unstemmed Silymarin modulates catabolic cytokine expression through Sirt1 and SOX9 in human articular chondrocytes
title_short Silymarin modulates catabolic cytokine expression through Sirt1 and SOX9 in human articular chondrocytes
title_sort silymarin modulates catabolic cytokine expression through sirt1 and sox9 in human articular chondrocytes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896383/
https://www.ncbi.nlm.nih.gov/pubmed/33610183
http://dx.doi.org/10.1186/s13018-021-02305-9
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