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  1. Artikel ; Online: Hippo-PKCζ-NFκB signaling axis: A druggable modulator of chondrocyte responses to mechanical stress.

    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

    iScience

    2024  Band 27, Heft 6, Seite(n) 109983

    Abstract: Recent studies have implicated a crucial role of Hippo signaling in cell fate determination by biomechanical signals. Here we show that mechanical loading triggers the activation of a Hippo-PKCζ-NFκB pathway in chondrocytes, resulting in the expression ... ...

    Abstract Recent studies have implicated a crucial role of Hippo signaling in cell fate determination by biomechanical signals. Here we show that mechanical loading triggers the activation of a Hippo-PKCζ-NFκB pathway in chondrocytes, resulting in the expression of NFκB target genes associated with inflammation and matrix degradation. Mechanistically, mechanical loading activates an atypical PKC, PKCζ, which phosphorylates NFκB p65 at Serine 536, stimulating its transcriptional activation. This mechanosensitive activation of PKCζ and NFκB p65 is impeded in cells with gene deletion or chemical inhibition of Hippo core kinases LATS1/2, signifying an essential role of Hippo signaling in this mechanotransduction. A PKC inhibitor AEB-071 or PKCζ knockdown prevents p65 Serine 536 phosphorylation. Our study uncovers that the interplay of the Hippo signaling, PKCζ, and NFκB in response to mechanical loading serves as a therapeutic target for knee osteoarthritis and other conditions resulting from mechanical overloading or Hippo signaling deficiencies.
    Sprache Englisch
    Erscheinungsdatum 2024-05-15
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2024.109983
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel: 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 : the preprint server for biology

    2023  

    Abstract: 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 ... ...

    Abstract 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., IL1
    Sprache Englisch
    Erscheinungsdatum 2023-06-11
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2023.06.09.544419
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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