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Reciprocal inhibition of YAP/TAZ and NF-κB regulates osteoarthritic cartilage degradation
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Reciprocal inhibition of YAP/TAZ and NF-κB regulates osteoarthritic cartilage degradation
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Journal Article
Reciprocal inhibition of YAP/TAZ and NF-κB regulates osteoarthritic cartilage degradation
2018
Overview
Osteoarthritis is one of the leading causes of pain and disability in the aged population due to articular cartilage damage. This warrants investigation of signaling mechanisms that could protect cartilage from degeneration and degradation. Here we show in a murine model of experimental osteoarthritis that YAP activation by transgenic overexpression or by deletion of its upstream inhibitory kinases Mst1/2 preserves articular cartilage integrity, whereas deletion of YAP in chondrocytes promotes cartilage disruption. Our work shows that YAP is both necessary and sufficient for the maintenance of cartilage homeostasis in osteoarthritis. Mechanistically, inflammatory cytokines, such as TNFα or IL-1β, trigger YAP/TAZ degradation through TAK1-mediated phosphorylation. Furthermore, YAP directly interacts with TAK1 and attenuates NF-κB signaling by inhibiting substrate accessibility of TAK1. Our study establishes a reciprocal antagonism between Hippo-YAP/TAZ and NF-κB signaling in regulating the induction of matrix-degrading enzyme expression and cartilage degradation during osteoarthritis pathogenesis.
Inflammation can promote cartilage degradation by inducing matrix-degrading enzymes via NF-κB. Here the authors uncover reciprocal inhibition of Yap/Taz and NF-κB signaling though TAK1, and identify Yap activity as critical for maintenance of cartilage integrity in a mouse model of osteoarthritis.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 64
/ 64/60
/ Adaptor Proteins, Signal Transducing - genetics
/ Animals
/ Cartilage, Articular - immunology
/ Cartilage, Articular - metabolism
/ Cartilage, Articular - pathology
/ Extracellular Matrix - metabolism
/ Humanities and Social Sciences
/ IL-1β
/ Interleukin-1beta - immunology
/ Kinases
/ MAP Kinase Kinase Kinases - metabolism
/ Matrix Metalloproteinases - metabolism
/ Mice
/ Pain
/ Protein-Serine-Threonine Kinases - genetics
/ Protein-Serine-Threonine Kinases - metabolism
/ Science
