Silencing <i>miR-146a-5p</i> 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...
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MDPI AG
2023-01-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/1/123 |
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| author | Haocheng Qin Cuicui Wang Yonghua He Aiwu Lu Tiandao Li Bo Zhang Jie Shen |
| author_facet | Haocheng Qin Cuicui Wang Yonghua He Aiwu Lu Tiandao Li Bo Zhang Jie Shen |
| author_sort | Haocheng Qin |
| collection | DOAJ |
| 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 <i>miR-146a-5p</i> as the most responsive miRNA to IL-1β. <i>miR-146a-5p</i> was also found to be upregulated in human OA cartilage. We further demonstrated that knockdown of <i>miR-146a-5p</i> antagonized IL-1β-mediated inflammatory responses and IL-1β-induced catabolism in vitro, and silencing of <i>miR-146a</i> 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 <i>miR-146a-5p</i> gene targets and following prediction of protein–protein interactions suggest a functional role of <i>miR-146a-5p</i> in mediating inflammatory processes and regulation of cartilage homeostasis. Our genetic and transcriptomic data define a crucial role of <i>miR-146a-5p</i> in OA pathogenesis and implicate modulation of <i>miR-146a-5p</i> in articular chondrocytes as a potential therapeutic strategy to alleviate OA. |
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| language | English |
| last_indexed | 2024-03-09T13:26:15Z |
| publishDate | 2023-01-01 |
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| spelling | doaj.art-63a2abd2c042457b904c7c5556ed461a2023-11-30T21:23:06ZengMDPI AGBiomolecules2218-273X2023-01-0113112310.3390/biom13010123Silencing <i>miR-146a-5p</i> Protects against Injury-Induced Osteoarthritis in MiceHaocheng Qin0Cuicui Wang1Yonghua He2Aiwu Lu3Tiandao Li4Bo Zhang5Jie Shen6Department of Orthopaedic Surgery, School of Medicine, Washington University, St. Louis, MO 63110, USADepartment of Orthopaedic Surgery, School of Medicine, Washington University, St. Louis, MO 63110, USADepartment of Orthopaedic Surgery, School of Medicine, Washington University, St. Louis, MO 63110, USADepartment of Orthopaedic Surgery, School of Medicine, Washington University, St. Louis, MO 63110, USADepartment of Developmental Biology, Center of Regenerative Medicine, Washington University, St. Louis, MO 63110, USADepartment of Developmental Biology, Center of Regenerative Medicine, Washington University, St. Louis, MO 63110, USADepartment of Orthopaedic Surgery, School of Medicine, Washington University, St. Louis, MO 63110, USAOsteoarthritis (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 <i>miR-146a-5p</i> as the most responsive miRNA to IL-1β. <i>miR-146a-5p</i> was also found to be upregulated in human OA cartilage. We further demonstrated that knockdown of <i>miR-146a-5p</i> antagonized IL-1β-mediated inflammatory responses and IL-1β-induced catabolism in vitro, and silencing of <i>miR-146a</i> 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 <i>miR-146a-5p</i> gene targets and following prediction of protein–protein interactions suggest a functional role of <i>miR-146a-5p</i> in mediating inflammatory processes and regulation of cartilage homeostasis. Our genetic and transcriptomic data define a crucial role of <i>miR-146a-5p</i> in OA pathogenesis and implicate modulation of <i>miR-146a-5p</i> in articular chondrocytes as a potential therapeutic strategy to alleviate OA.https://www.mdpi.com/2218-273X/13/1/123osteoarthritisarticular chondrocyteinflammation<i>miR-146a-5p</i> |
| spellingShingle | Haocheng Qin Cuicui Wang Yonghua He Aiwu Lu Tiandao Li Bo Zhang Jie Shen Silencing <i>miR-146a-5p</i> Protects against Injury-Induced Osteoarthritis in Mice Biomolecules osteoarthritis articular chondrocyte inflammation <i>miR-146a-5p</i> |
| title | Silencing <i>miR-146a-5p</i> Protects against Injury-Induced Osteoarthritis in Mice |
| title_full | Silencing <i>miR-146a-5p</i> Protects against Injury-Induced Osteoarthritis in Mice |
| title_fullStr | Silencing <i>miR-146a-5p</i> Protects against Injury-Induced Osteoarthritis in Mice |
| title_full_unstemmed | Silencing <i>miR-146a-5p</i> Protects against Injury-Induced Osteoarthritis in Mice |
| title_short | Silencing <i>miR-146a-5p</i> Protects against Injury-Induced Osteoarthritis in Mice |
| title_sort | silencing i mir 146a 5p i protects against injury induced osteoarthritis in mice |
| topic | osteoarthritis articular chondrocyte inflammation <i>miR-146a-5p</i> |
| url | https://www.mdpi.com/2218-273X/13/1/123 |
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