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Effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the osteoarthritis rabbit model

BACKGROUND: The use of interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor as a treatment for the inflammatory joint disease is a promising method. However, its underlying mechanism in osteoarthritis (OA) remains unclear. The purpose of this study is to look into the effects of adenovirus-m...

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Autores principales: Li, Muzhe, Li, Huiyun, Ran, Xun, Yin, Han, Luo, Xuling, Chen, Zhiwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8643028/
https://www.ncbi.nlm.nih.gov/pubmed/34863246
http://dx.doi.org/10.1186/s13075-021-02684-8
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author Li, Muzhe
Li, Huiyun
Ran, Xun
Yin, Han
Luo, Xuling
Chen, Zhiwei
author_facet Li, Muzhe
Li, Huiyun
Ran, Xun
Yin, Han
Luo, Xuling
Chen, Zhiwei
author_sort Li, Muzhe
collection PubMed
description BACKGROUND: The use of interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor as a treatment for the inflammatory joint disease is a promising method. However, its underlying mechanism in osteoarthritis (OA) remains unclear. The purpose of this study is to look into the effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the OA rabbit model. METHODS: Ad-shIRAK4 was injected two weeks after anterior cruciate ligament resection. Six weeks later, the rabbits were killed. The expression of IRAK4, TNFR-associated factor 6(TRAF6), TGF-activated kinase 1(TAK1), p-IKB kinase (p-IKK), p-nuclear factor kappa-B (p-NFκB), p38, and p-p38 in the synovial membrane was detected by western blot, qRT-PCR, and immunohistochemistry analysis. Immunohistochemistry was to detect the expression of IRAK4 proteins in articular cartilage. H&E staining was to assess the pathological changes of synovium and cartilage. The levels of interleukin (IL)-1β, tumor necrosis factor-α(TNF-α), and MMP-13 in the synovial fluid were measured by ELISA. X-ray and micro-computerized tomography (μCT) scans were used to assess knee joint conditions and microstructure of subchondral bone. RESULTS: IRAK4 expression levels in synovial tissues of the OA model group exhibited a significant upward trend. Ad-shIRAK4 significantly reduced IRAK4 mRNA expression in synovium tissues. Notably, Ad-shIRAK4 suppressed the Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) signaling. In addition, in the Ad-shIRAK4 treatment group, we can see less inflammatory cell infiltration and reduced hyperplasia and angiogenesis. The levels of IL-1β, TNF-α, and MMP-13 in the synovial fluid in the OA model group were significantly higher than that in the control group, which were reduced by Ad-shIRAK4 treatment. Finally, Results of HE stains, immunohistochemistry, and μCT showed that Ad-shIRAK4 treatment has a protective effect on cartilage damage. CONCLUSIONS: IRAK4 is significantly upregulated in the synovium from the osteoarthritis rabbit model. In addition, Ad-shIRAK4 reduced the expression of IRAK4 and suppressed TLR/IL-1R signaling in the synovium from the osteoarthritis rabbit model. Ad-shIRAK4 could alleviate synovitis and cartilage degradation in the osteoarthritis rabbit model, and thus alleviate the symptoms of OA and prevent the progression of OA. GRAPHICAL ABSTRACT: [Image: see text]
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spelling pubmed-86430282021-12-06 Effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the osteoarthritis rabbit model Li, Muzhe Li, Huiyun Ran, Xun Yin, Han Luo, Xuling Chen, Zhiwei Arthritis Res Ther Research Article BACKGROUND: The use of interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor as a treatment for the inflammatory joint disease is a promising method. However, its underlying mechanism in osteoarthritis (OA) remains unclear. The purpose of this study is to look into the effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the OA rabbit model. METHODS: Ad-shIRAK4 was injected two weeks after anterior cruciate ligament resection. Six weeks later, the rabbits were killed. The expression of IRAK4, TNFR-associated factor 6(TRAF6), TGF-activated kinase 1(TAK1), p-IKB kinase (p-IKK), p-nuclear factor kappa-B (p-NFκB), p38, and p-p38 in the synovial membrane was detected by western blot, qRT-PCR, and immunohistochemistry analysis. Immunohistochemistry was to detect the expression of IRAK4 proteins in articular cartilage. H&E staining was to assess the pathological changes of synovium and cartilage. The levels of interleukin (IL)-1β, tumor necrosis factor-α(TNF-α), and MMP-13 in the synovial fluid were measured by ELISA. X-ray and micro-computerized tomography (μCT) scans were used to assess knee joint conditions and microstructure of subchondral bone. RESULTS: IRAK4 expression levels in synovial tissues of the OA model group exhibited a significant upward trend. Ad-shIRAK4 significantly reduced IRAK4 mRNA expression in synovium tissues. Notably, Ad-shIRAK4 suppressed the Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) signaling. In addition, in the Ad-shIRAK4 treatment group, we can see less inflammatory cell infiltration and reduced hyperplasia and angiogenesis. The levels of IL-1β, TNF-α, and MMP-13 in the synovial fluid in the OA model group were significantly higher than that in the control group, which were reduced by Ad-shIRAK4 treatment. Finally, Results of HE stains, immunohistochemistry, and μCT showed that Ad-shIRAK4 treatment has a protective effect on cartilage damage. CONCLUSIONS: IRAK4 is significantly upregulated in the synovium from the osteoarthritis rabbit model. In addition, Ad-shIRAK4 reduced the expression of IRAK4 and suppressed TLR/IL-1R signaling in the synovium from the osteoarthritis rabbit model. Ad-shIRAK4 could alleviate synovitis and cartilage degradation in the osteoarthritis rabbit model, and thus alleviate the symptoms of OA and prevent the progression of OA. GRAPHICAL ABSTRACT: [Image: see text] BioMed Central 2021-12-04 2021 /pmc/articles/PMC8643028/ /pubmed/34863246 http://dx.doi.org/10.1186/s13075-021-02684-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://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
Li, Muzhe
Li, Huiyun
Ran, Xun
Yin, Han
Luo, Xuling
Chen, Zhiwei
Effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the osteoarthritis rabbit model
title Effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the osteoarthritis rabbit model
title_full Effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the osteoarthritis rabbit model
title_fullStr Effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the osteoarthritis rabbit model
title_full_unstemmed Effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the osteoarthritis rabbit model
title_short Effects of adenovirus-mediated knockdown of IRAK4 on synovitis in the osteoarthritis rabbit model
title_sort effects of adenovirus-mediated knockdown of irak4 on synovitis in the osteoarthritis rabbit model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8643028/
https://www.ncbi.nlm.nih.gov/pubmed/34863246
http://dx.doi.org/10.1186/s13075-021-02684-8
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