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Silencing miR-146a-5p Protects against Injury-Induced Osteoarthritis in Mice
Osteoarthritis (OA), the most prevalent joint disease and the leading cause of disability, remains an incurable disease largely because the etiology and pathogenesis underlying this degenerative process are poorly understood. Low-grade inflammation within joints is a well-established factor that dis...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9856058/ https://www.ncbi.nlm.nih.gov/pubmed/36671508 http://dx.doi.org/10.3390/biom13010123 |
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author | Qin, Haocheng Wang, Cuicui He, Yonghua Lu, Aiwu Li, Tiandao Zhang, Bo Shen, Jie |
author_facet | Qin, Haocheng Wang, Cuicui He, Yonghua Lu, Aiwu Li, Tiandao Zhang, Bo Shen, Jie |
author_sort | Qin, Haocheng |
collection | PubMed |
description | Osteoarthritis (OA), the most prevalent joint disease and the leading cause of disability, remains an incurable disease largely because the etiology and pathogenesis underlying this degenerative process are poorly understood. Low-grade inflammation within joints is a well-established factor that disturbs joint homeostasis and leads to an imbalance between anabolic and catabolic processes in articular cartilage; however, the complexity of the network between inflammatory factors that often involves positive and negative feedback loops makes current anti-cytokine therapy ineffective. MicroRNAs (miRNAs) have emerged as key regulators to control inflammation, and aberrant miRNAs expression has recently been linked to OA pathophysiology. In the present study, we characterized transcriptomic profiles of miRNAs in primary murine articular chondrocytes in response to a proinflammatory cytokine, IL-1β, and identified miR-146a-5p as the most responsive miRNA to IL-1β. miR-146a-5p was also found to be upregulated in human OA cartilage. We further demonstrated that knockdown of miR-146a-5p antagonized IL-1β-mediated inflammatory responses and IL-1β-induced catabolism in vitro, and silencing of miR-146a in chondrocytes ameliorated articular cartilage destruction and reduced OA-evoked pain in an injury-induced murine OA model. Moreover, parallel RNA sequencing revealed that differentially expressed genes in response to IL-1β were enriched in pathways related to inflammatory processes, cartilage matrix homeostasis, and cell metabolism. Bioinformatic analyses of putative miR-146a-5p gene targets and following prediction of protein–protein interactions suggest a functional role of miR-146a-5p in mediating inflammatory processes and regulation of cartilage homeostasis. Our genetic and transcriptomic data define a crucial role of miR-146a-5p in OA pathogenesis and implicate modulation of miR-146a-5p in articular chondrocytes as a potential therapeutic strategy to alleviate OA. |
format | Online Article Text |
id | pubmed-9856058 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-98560582023-01-21 Silencing miR-146a-5p Protects against Injury-Induced Osteoarthritis in Mice Qin, Haocheng Wang, Cuicui He, Yonghua Lu, Aiwu Li, Tiandao Zhang, Bo Shen, Jie Biomolecules Article Osteoarthritis (OA), the most prevalent joint disease and the leading cause of disability, remains an incurable disease largely because the etiology and pathogenesis underlying this degenerative process are poorly understood. Low-grade inflammation within joints is a well-established factor that disturbs joint homeostasis and leads to an imbalance between anabolic and catabolic processes in articular cartilage; however, the complexity of the network between inflammatory factors that often involves positive and negative feedback loops makes current anti-cytokine therapy ineffective. MicroRNAs (miRNAs) have emerged as key regulators to control inflammation, and aberrant miRNAs expression has recently been linked to OA pathophysiology. In the present study, we characterized transcriptomic profiles of miRNAs in primary murine articular chondrocytes in response to a proinflammatory cytokine, IL-1β, and identified miR-146a-5p as the most responsive miRNA to IL-1β. miR-146a-5p was also found to be upregulated in human OA cartilage. We further demonstrated that knockdown of miR-146a-5p antagonized IL-1β-mediated inflammatory responses and IL-1β-induced catabolism in vitro, and silencing of miR-146a in chondrocytes ameliorated articular cartilage destruction and reduced OA-evoked pain in an injury-induced murine OA model. Moreover, parallel RNA sequencing revealed that differentially expressed genes in response to IL-1β were enriched in pathways related to inflammatory processes, cartilage matrix homeostasis, and cell metabolism. Bioinformatic analyses of putative miR-146a-5p gene targets and following prediction of protein–protein interactions suggest a functional role of miR-146a-5p in mediating inflammatory processes and regulation of cartilage homeostasis. Our genetic and transcriptomic data define a crucial role of miR-146a-5p in OA pathogenesis and implicate modulation of miR-146a-5p in articular chondrocytes as a potential therapeutic strategy to alleviate OA. MDPI 2023-01-07 /pmc/articles/PMC9856058/ /pubmed/36671508 http://dx.doi.org/10.3390/biom13010123 Text en © 2023 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 Qin, Haocheng Wang, Cuicui He, Yonghua Lu, Aiwu Li, Tiandao Zhang, Bo Shen, Jie Silencing miR-146a-5p Protects against Injury-Induced Osteoarthritis in Mice |
title | Silencing miR-146a-5p Protects against Injury-Induced Osteoarthritis in Mice |
title_full | Silencing miR-146a-5p Protects against Injury-Induced Osteoarthritis in Mice |
title_fullStr | Silencing miR-146a-5p Protects against Injury-Induced Osteoarthritis in Mice |
title_full_unstemmed | Silencing miR-146a-5p Protects against Injury-Induced Osteoarthritis in Mice |
title_short | Silencing miR-146a-5p Protects against Injury-Induced Osteoarthritis in Mice |
title_sort | silencing mir-146a-5p protects against injury-induced osteoarthritis in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9856058/ https://www.ncbi.nlm.nih.gov/pubmed/36671508 http://dx.doi.org/10.3390/biom13010123 |
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