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Friedelin Alleviates the Pathogenesis of Collagenase-Induced Tendinopathy in Mice by Promoting the Selective Autophagic Degradation of p65

With the development of an aging population, tendinopathy has become a common musculoskeletal disease in the elderly with a high recurrence rate and no curative treatment. The inflammation mediated by NF-κB signaling plays an important role in tendon senescence and degeneration. Friedelin (FR) is a...

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Autores principales: Jiang, Huaji, Lin, Xuemei, Liang, Wei, Li, Yiqiang, Yu, Xiao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9031956/
https://www.ncbi.nlm.nih.gov/pubmed/35458235
http://dx.doi.org/10.3390/nu14081673
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author Jiang, Huaji
Lin, Xuemei
Liang, Wei
Li, Yiqiang
Yu, Xiao
author_facet Jiang, Huaji
Lin, Xuemei
Liang, Wei
Li, Yiqiang
Yu, Xiao
author_sort Jiang, Huaji
collection PubMed
description With the development of an aging population, tendinopathy has become a common musculoskeletal disease in the elderly with a high recurrence rate and no curative treatment. The inflammation mediated by NF-κB signaling plays an important role in tendon senescence and degeneration. Friedelin (FR) is a triterpenoid derived from green plants, which has a variety of pharmacological functions, such as analgesia, anti-inflammation, antioxidation, and anti-tumor functions. However, the role and mechanism of FR in tendinopathy are unclear. Here, we found that FR improved the mechanical strength of the Achilles tendon, restored the orderly arrangement of collagen fibers, reduced inflammatory cell infiltration, and promoted tenogenesis, thereby blocking the progression of tendinopathy. Mechanistically, FR promoted the autophagic degradation of p65 by enhancing the interaction between p62 and p65 and effectively inhibited the activation of the NF-κB pathway, thus alleviating the inflammatory response of tenocytes. In addition, FR recruited E3 ubiquitin enzyme RNF182 to increase the K48-linked ubiquitination of p65 and promoted p62-mediated autophagic degradation. Furthermore, blocking ubiquitination reversed the degradation of p65 by FR. Therefore, these findings identify the new pharmacological mechanism of the anti-inflammatory effect of FR and provide a new candidate drug for the treatment of tendinopathy.
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spelling pubmed-90319562022-04-23 Friedelin Alleviates the Pathogenesis of Collagenase-Induced Tendinopathy in Mice by Promoting the Selective Autophagic Degradation of p65 Jiang, Huaji Lin, Xuemei Liang, Wei Li, Yiqiang Yu, Xiao Nutrients Article With the development of an aging population, tendinopathy has become a common musculoskeletal disease in the elderly with a high recurrence rate and no curative treatment. The inflammation mediated by NF-κB signaling plays an important role in tendon senescence and degeneration. Friedelin (FR) is a triterpenoid derived from green plants, which has a variety of pharmacological functions, such as analgesia, anti-inflammation, antioxidation, and anti-tumor functions. However, the role and mechanism of FR in tendinopathy are unclear. Here, we found that FR improved the mechanical strength of the Achilles tendon, restored the orderly arrangement of collagen fibers, reduced inflammatory cell infiltration, and promoted tenogenesis, thereby blocking the progression of tendinopathy. Mechanistically, FR promoted the autophagic degradation of p65 by enhancing the interaction between p62 and p65 and effectively inhibited the activation of the NF-κB pathway, thus alleviating the inflammatory response of tenocytes. In addition, FR recruited E3 ubiquitin enzyme RNF182 to increase the K48-linked ubiquitination of p65 and promoted p62-mediated autophagic degradation. Furthermore, blocking ubiquitination reversed the degradation of p65 by FR. Therefore, these findings identify the new pharmacological mechanism of the anti-inflammatory effect of FR and provide a new candidate drug for the treatment of tendinopathy. MDPI 2022-04-18 /pmc/articles/PMC9031956/ /pubmed/35458235 http://dx.doi.org/10.3390/nu14081673 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
Jiang, Huaji
Lin, Xuemei
Liang, Wei
Li, Yiqiang
Yu, Xiao
Friedelin Alleviates the Pathogenesis of Collagenase-Induced Tendinopathy in Mice by Promoting the Selective Autophagic Degradation of p65
title Friedelin Alleviates the Pathogenesis of Collagenase-Induced Tendinopathy in Mice by Promoting the Selective Autophagic Degradation of p65
title_full Friedelin Alleviates the Pathogenesis of Collagenase-Induced Tendinopathy in Mice by Promoting the Selective Autophagic Degradation of p65
title_fullStr Friedelin Alleviates the Pathogenesis of Collagenase-Induced Tendinopathy in Mice by Promoting the Selective Autophagic Degradation of p65
title_full_unstemmed Friedelin Alleviates the Pathogenesis of Collagenase-Induced Tendinopathy in Mice by Promoting the Selective Autophagic Degradation of p65
title_short Friedelin Alleviates the Pathogenesis of Collagenase-Induced Tendinopathy in Mice by Promoting the Selective Autophagic Degradation of p65
title_sort friedelin alleviates the pathogenesis of collagenase-induced tendinopathy in mice by promoting the selective autophagic degradation of p65
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9031956/
https://www.ncbi.nlm.nih.gov/pubmed/35458235
http://dx.doi.org/10.3390/nu14081673
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