Reciprocal inhibition of YAP/TAZ and NF-κB regulates osteoarthritic cartilage degradation

Yujie Deng, Jinqiu Lu, Wenling Li, Ailing Wu, Xu Zhang, Wenxue Tong, Kiwai Kevin Ho, Ling Qin, Hai Song () and Kinglun Kingston Mak ()
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Yujie Deng: Zhejiang University
Jinqiu Lu: Zhejiang University
Wenling Li: The Chinese University of Hong Kong
Ailing Wu: Zhejiang University
Xu Zhang: The Chinese University of Hong Kong
Wenxue Tong: The Chinese University of Hong Kong
Kiwai Kevin Ho: The Chinese University of Hong Kong
Ling Qin: The Chinese University of Hong Kong
Hai Song: Zhejiang University
Kinglun Kingston Mak: The Chinese University of Hong Kong

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-07022-2

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