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Inhibition of NADPH Oxidases Prevents the Development of Osteoarthritis

Increased oxidative stress in osteoarthritis (OA) cartilage mediates catabolic signal transduction leading to extracellular matrix degradation and chondrocyte apoptosis. This study aimed to explore the contribution of NADPH oxidase (NOX), a major source of cellular reactive oxygen species (ROS), to...

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Autores principales: Han, Jin, Park, Donghwi, Park, Ji Young, Han, Seungwoo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9774355/
https://www.ncbi.nlm.nih.gov/pubmed/36552552
http://dx.doi.org/10.3390/antiox11122346
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author Han, Jin
Park, Donghwi
Park, Ji Young
Han, Seungwoo
author_facet Han, Jin
Park, Donghwi
Park, Ji Young
Han, Seungwoo
author_sort Han, Jin
collection PubMed
description Increased oxidative stress in osteoarthritis (OA) cartilage mediates catabolic signal transduction leading to extracellular matrix degradation and chondrocyte apoptosis. This study aimed to explore the contribution of NADPH oxidase (NOX), a major source of cellular reactive oxygen species (ROS), to the catabolic process of chondrocytes and to OA. The inhibition of NOX isoforms with a pan-NOX inhibitor, APX-115, significantly decreased IL-1β-induced ROS production in primary chondrocytes and, most potently, suppressed the expression of oxidative stress marker genes and catabolic proteases compared with the inhibition of other ROS sources. Catabolic stimuli by IL-1β treatment and in post-traumatic OA conditions upregulated the expression of NOX2 and NOX4 in chondrocytes. In the post-traumatic OA model, the pharmacologic inhibition of NOX protected mice against OA by modulating the oxidative stress and the expression of MMP-13 and Adamts5 in chondrocytes. Mechanistically, NOX inhibition suppresses Rac1, p38, and JNK MAPK signaling consistently and restores oxidative phosphorylation in IL-1β-treated chondrocytes. In conclusion, NOX inhibition prevented the development of OA by attenuating the catabolic signaling and restoring the mitochondrial metabolism and can thus be a promising class of drug for OA.
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spelling pubmed-97743552022-12-23 Inhibition of NADPH Oxidases Prevents the Development of Osteoarthritis Han, Jin Park, Donghwi Park, Ji Young Han, Seungwoo Antioxidants (Basel) Article Increased oxidative stress in osteoarthritis (OA) cartilage mediates catabolic signal transduction leading to extracellular matrix degradation and chondrocyte apoptosis. This study aimed to explore the contribution of NADPH oxidase (NOX), a major source of cellular reactive oxygen species (ROS), to the catabolic process of chondrocytes and to OA. The inhibition of NOX isoforms with a pan-NOX inhibitor, APX-115, significantly decreased IL-1β-induced ROS production in primary chondrocytes and, most potently, suppressed the expression of oxidative stress marker genes and catabolic proteases compared with the inhibition of other ROS sources. Catabolic stimuli by IL-1β treatment and in post-traumatic OA conditions upregulated the expression of NOX2 and NOX4 in chondrocytes. In the post-traumatic OA model, the pharmacologic inhibition of NOX protected mice against OA by modulating the oxidative stress and the expression of MMP-13 and Adamts5 in chondrocytes. Mechanistically, NOX inhibition suppresses Rac1, p38, and JNK MAPK signaling consistently and restores oxidative phosphorylation in IL-1β-treated chondrocytes. In conclusion, NOX inhibition prevented the development of OA by attenuating the catabolic signaling and restoring the mitochondrial metabolism and can thus be a promising class of drug for OA. MDPI 2022-11-27 /pmc/articles/PMC9774355/ /pubmed/36552552 http://dx.doi.org/10.3390/antiox11122346 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Han, Jin
Park, Donghwi
Park, Ji Young
Han, Seungwoo
Inhibition of NADPH Oxidases Prevents the Development of Osteoarthritis
title Inhibition of NADPH Oxidases Prevents the Development of Osteoarthritis
title_full Inhibition of NADPH Oxidases Prevents the Development of Osteoarthritis
title_fullStr Inhibition of NADPH Oxidases Prevents the Development of Osteoarthritis
title_full_unstemmed Inhibition of NADPH Oxidases Prevents the Development of Osteoarthritis
title_short Inhibition of NADPH Oxidases Prevents the Development of Osteoarthritis
title_sort inhibition of nadph oxidases prevents the development of osteoarthritis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9774355/
https://www.ncbi.nlm.nih.gov/pubmed/36552552
http://dx.doi.org/10.3390/antiox11122346
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