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Downregulation of Sox8 mediates monosodium urate crystal-induced autophagic impairment of cartilage in gout arthritis

The deposition of monosodium urate (MSU) crystals in arthritic joints of gout seriously damages cartilage. This study aimed to investigate whether MSU crystal-induced cartilage impairment was related to autophagic signaling. mRNAs of cartilage from MSU-induced gouty arthritis rat model were sequence...

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Autores principales: Xiao, Lu, Lin, Shudian, Xu, WenChao, Sun, Erwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10015026/
https://www.ncbi.nlm.nih.gov/pubmed/36918540
http://dx.doi.org/10.1038/s41420-023-01388-z
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author Xiao, Lu
Lin, Shudian
Xu, WenChao
Sun, Erwei
author_facet Xiao, Lu
Lin, Shudian
Xu, WenChao
Sun, Erwei
author_sort Xiao, Lu
collection PubMed
description The deposition of monosodium urate (MSU) crystals in arthritic joints of gout seriously damages cartilage. This study aimed to investigate whether MSU crystal-induced cartilage impairment was related to autophagic signaling. mRNAs of cartilage from MSU-induced gouty arthritis rat model were sequenced. MSU crystal-treated human chondrocytes were used to evaluate the function of Sox8. The recombinant Sox8 lentiviral vector (lenti-Sox8) was applied to upregulate the expression of Sox8. Transfection of the mRFP-GFP-LC3 plasmid was evaluated by confocal microscopy. The autophagic vacuoles were stained with monodansylcadaverine and examined by flow cytometry. The morphology of autophagosomes was observed by transmission electron microscopy. The ratio of LC3-II/I in the presence or absence of bafilomycin A1 and the expression levels of Beclin1, Sox8, p-PI3K, PI3K, p-AKT, AKT, p-mTOR, and mTOR were detected by Western blot. In vivo, the effect of Sox8 on cartilage of acute gouty model rats was evaluated by safranin-O/fast green staining and Western blot. The expression of Sox8 was significantly downregulated both in vivo and in vitro. In chondrocytes, MSU crystals reduced the expression of Sox8, inhibited the PI3K/AKT/mTOR signaling pathway, and increased the level of autophagy. Overexpression of Sox8 notably inhibited MSU crystal-induced autophagy by rescuing the phosphorylation levels in the PI3K/AKT/mTOR signaling pathway. In vivo, overexpression of Sox8 remarkably alleviated cartilage damage in acute gouty model rats. These results indicate that downregulation of Sox8 plays an important role in MSU-induced chondrocyte autophagy by modulating PI3K/AKT/mTOR signaling, and overexpression of Sox8 may serve as a novel therapy to prevent the impairment of cartilage in gout arthritis.
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spelling pubmed-100150262023-03-16 Downregulation of Sox8 mediates monosodium urate crystal-induced autophagic impairment of cartilage in gout arthritis Xiao, Lu Lin, Shudian Xu, WenChao Sun, Erwei Cell Death Discov Article The deposition of monosodium urate (MSU) crystals in arthritic joints of gout seriously damages cartilage. This study aimed to investigate whether MSU crystal-induced cartilage impairment was related to autophagic signaling. mRNAs of cartilage from MSU-induced gouty arthritis rat model were sequenced. MSU crystal-treated human chondrocytes were used to evaluate the function of Sox8. The recombinant Sox8 lentiviral vector (lenti-Sox8) was applied to upregulate the expression of Sox8. Transfection of the mRFP-GFP-LC3 plasmid was evaluated by confocal microscopy. The autophagic vacuoles were stained with monodansylcadaverine and examined by flow cytometry. The morphology of autophagosomes was observed by transmission electron microscopy. The ratio of LC3-II/I in the presence or absence of bafilomycin A1 and the expression levels of Beclin1, Sox8, p-PI3K, PI3K, p-AKT, AKT, p-mTOR, and mTOR were detected by Western blot. In vivo, the effect of Sox8 on cartilage of acute gouty model rats was evaluated by safranin-O/fast green staining and Western blot. The expression of Sox8 was significantly downregulated both in vivo and in vitro. In chondrocytes, MSU crystals reduced the expression of Sox8, inhibited the PI3K/AKT/mTOR signaling pathway, and increased the level of autophagy. Overexpression of Sox8 notably inhibited MSU crystal-induced autophagy by rescuing the phosphorylation levels in the PI3K/AKT/mTOR signaling pathway. In vivo, overexpression of Sox8 remarkably alleviated cartilage damage in acute gouty model rats. These results indicate that downregulation of Sox8 plays an important role in MSU-induced chondrocyte autophagy by modulating PI3K/AKT/mTOR signaling, and overexpression of Sox8 may serve as a novel therapy to prevent the impairment of cartilage in gout arthritis. Nature Publishing Group UK 2023-03-14 /pmc/articles/PMC10015026/ /pubmed/36918540 http://dx.doi.org/10.1038/s41420-023-01388-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Xiao, Lu
Lin, Shudian
Xu, WenChao
Sun, Erwei
Downregulation of Sox8 mediates monosodium urate crystal-induced autophagic impairment of cartilage in gout arthritis
title Downregulation of Sox8 mediates monosodium urate crystal-induced autophagic impairment of cartilage in gout arthritis
title_full Downregulation of Sox8 mediates monosodium urate crystal-induced autophagic impairment of cartilage in gout arthritis
title_fullStr Downregulation of Sox8 mediates monosodium urate crystal-induced autophagic impairment of cartilage in gout arthritis
title_full_unstemmed Downregulation of Sox8 mediates monosodium urate crystal-induced autophagic impairment of cartilage in gout arthritis
title_short Downregulation of Sox8 mediates monosodium urate crystal-induced autophagic impairment of cartilage in gout arthritis
title_sort downregulation of sox8 mediates monosodium urate crystal-induced autophagic impairment of cartilage in gout arthritis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10015026/
https://www.ncbi.nlm.nih.gov/pubmed/36918540
http://dx.doi.org/10.1038/s41420-023-01388-z
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