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Hippo Signaling Modulates the Inflammatory Response of Chondrocytes to Mechanical Compressive Loading
Knee osteoarthritis (KOA) is a degenerative disease resulting from mechanical overload, where direct physical impacts on chondrocytes play a crucial role in disease development by inducing inflammation and extracellular matrix degradation. However, the signaling cascades that sense these physical im...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10473729/ https://www.ncbi.nlm.nih.gov/pubmed/37662374 http://dx.doi.org/10.1101/2023.06.09.544419 |
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author | Cai, Xiaomin Warburton, Christopher Perez, Olivia F. Wang, Ying Ho, Lucy Finelli, Christina Ehlen, Quinn T. Wu, Chenzhou Rodriguez, Carlos D. Kaplan, Lee Best, Thomas M. Huang, Chun-Yuh Meng, Zhipeng |
author_facet | Cai, Xiaomin Warburton, Christopher Perez, Olivia F. Wang, Ying Ho, Lucy Finelli, Christina Ehlen, Quinn T. Wu, Chenzhou Rodriguez, Carlos D. Kaplan, Lee Best, Thomas M. Huang, Chun-Yuh Meng, Zhipeng |
author_sort | Cai, Xiaomin |
collection | PubMed |
description | Knee osteoarthritis (KOA) is a degenerative disease resulting from mechanical overload, where direct physical impacts on chondrocytes play a crucial role in disease development by inducing inflammation and extracellular matrix degradation. However, the signaling cascades that sense these physical impacts and induce the pathogenic transcriptional programs of KOA remain to be defined, which hinders the identification of novel therapeutic approaches. Recent studies have implicated a crucial role of Hippo signaling in osteoarthritis. Since Hippo signaling senses mechanical cues, we aimed to determine its role in chondrocyte responses to mechanical overload. Here we show that mechanical loading induces the expression of inflammatory and matrix-degrading genes by activating the nuclear factor-kappaB (NFκB) pathway in a Hippo-dependent manner. Applying mechanical compressional force to 3-dimensional cultured chondrocytes activated NFκB and induced the expression of NFκB target genes for inflammation and matrix degradation (i.e., IL1β and ADAMTS4). Interestingly, deleting the Hippo pathway effector YAP or activating YAP by deleting core Hippo kinases LATS1/2 blocked the NFκB pathway activation induced by mechanical loading. Consistently, treatment with a LATS1/2 kinase inhibitor abolished the upregulation of IL1β and ADAMTS4 caused by mechanical loading. Mechanistically, mechanical loading activates Protein Kinase C (PKC), which activates NFκB p65 by phosphorylating its Serine 536. Furthermore, the mechano-activation of both PKC and NFκB p65 is blocked in LATS1/2 or YAP knockout cells, indicating that the Hippo pathway is required by this mechanoregulation. Additionally, the mechanical loading-induced phosphorylation of NFκB p65 at Ser536 is blocked by the LATS1/2 inhibitor Lats-In-1 or the PKC inhibitor AEB-071. Our study suggests that the interplay of the Hippo signaling and PKC controls NFκB-mediated inflammation and matrix degradation in response to mechanical loading. Chemical inhibitors targeting Hippo signaling or PKC can prevent the mechanoresponses of chondrocytes associated with inflammation and matrix degradation, providing a novel therapeutic strategy for KOA. |
format | Online Article Text |
id | pubmed-10473729 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-104737292023-09-02 Hippo Signaling Modulates the Inflammatory Response of Chondrocytes to Mechanical Compressive Loading Cai, Xiaomin Warburton, Christopher Perez, Olivia F. Wang, Ying Ho, Lucy Finelli, Christina Ehlen, Quinn T. Wu, Chenzhou Rodriguez, Carlos D. Kaplan, Lee Best, Thomas M. Huang, Chun-Yuh Meng, Zhipeng bioRxiv Article Knee osteoarthritis (KOA) is a degenerative disease resulting from mechanical overload, where direct physical impacts on chondrocytes play a crucial role in disease development by inducing inflammation and extracellular matrix degradation. However, the signaling cascades that sense these physical impacts and induce the pathogenic transcriptional programs of KOA remain to be defined, which hinders the identification of novel therapeutic approaches. Recent studies have implicated a crucial role of Hippo signaling in osteoarthritis. Since Hippo signaling senses mechanical cues, we aimed to determine its role in chondrocyte responses to mechanical overload. Here we show that mechanical loading induces the expression of inflammatory and matrix-degrading genes by activating the nuclear factor-kappaB (NFκB) pathway in a Hippo-dependent manner. Applying mechanical compressional force to 3-dimensional cultured chondrocytes activated NFκB and induced the expression of NFκB target genes for inflammation and matrix degradation (i.e., IL1β and ADAMTS4). Interestingly, deleting the Hippo pathway effector YAP or activating YAP by deleting core Hippo kinases LATS1/2 blocked the NFκB pathway activation induced by mechanical loading. Consistently, treatment with a LATS1/2 kinase inhibitor abolished the upregulation of IL1β and ADAMTS4 caused by mechanical loading. Mechanistically, mechanical loading activates Protein Kinase C (PKC), which activates NFκB p65 by phosphorylating its Serine 536. Furthermore, the mechano-activation of both PKC and NFκB p65 is blocked in LATS1/2 or YAP knockout cells, indicating that the Hippo pathway is required by this mechanoregulation. Additionally, the mechanical loading-induced phosphorylation of NFκB p65 at Ser536 is blocked by the LATS1/2 inhibitor Lats-In-1 or the PKC inhibitor AEB-071. Our study suggests that the interplay of the Hippo signaling and PKC controls NFκB-mediated inflammation and matrix degradation in response to mechanical loading. Chemical inhibitors targeting Hippo signaling or PKC can prevent the mechanoresponses of chondrocytes associated with inflammation and matrix degradation, providing a novel therapeutic strategy for KOA. Cold Spring Harbor Laboratory 2023-06-11 /pmc/articles/PMC10473729/ /pubmed/37662374 http://dx.doi.org/10.1101/2023.06.09.544419 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article Cai, Xiaomin Warburton, Christopher Perez, Olivia F. Wang, Ying Ho, Lucy Finelli, Christina Ehlen, Quinn T. Wu, Chenzhou Rodriguez, Carlos D. Kaplan, Lee Best, Thomas M. Huang, Chun-Yuh Meng, Zhipeng Hippo Signaling Modulates the Inflammatory Response of Chondrocytes to Mechanical Compressive Loading |
title | Hippo Signaling Modulates the Inflammatory Response of Chondrocytes to Mechanical Compressive Loading |
title_full | Hippo Signaling Modulates the Inflammatory Response of Chondrocytes to Mechanical Compressive Loading |
title_fullStr | Hippo Signaling Modulates the Inflammatory Response of Chondrocytes to Mechanical Compressive Loading |
title_full_unstemmed | Hippo Signaling Modulates the Inflammatory Response of Chondrocytes to Mechanical Compressive Loading |
title_short | Hippo Signaling Modulates the Inflammatory Response of Chondrocytes to Mechanical Compressive Loading |
title_sort | hippo signaling modulates the inflammatory response of chondrocytes to mechanical compressive loading |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10473729/ https://www.ncbi.nlm.nih.gov/pubmed/37662374 http://dx.doi.org/10.1101/2023.06.09.544419 |
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