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

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.

YAP1 inhibits the induction of TNF‐α‐stimulated bone‐resorbing mediators by suppressing the NF‐κB signaling pathway in MC3T3‐E1 cells

“…Then, NF‐κB translocates into the nucleus, where it mediates the transcription of various target genes (Vallabhapurapu & Karin, ). YAP associates with TAK1 and attenuates NF‐κB signaling in osteoarthritis (Deng et al, ). In our study, the expression of phosphorylated‐p65 S536 protein, the luciferase activity of the NF‐κB reporter, and the nuclear translocation of p65 decreased after YAP1 induction.…”

“…YAP/TAZ play crucial roles in regulating inflammation‐related diseases, such as osteoarthritis (Gong et al, ) and periodontitis (W. Pan et al, ), which are characterized by cartilage or bone destruction and resorption. YAP activation or deletion of the upstream regulators Mst1/2 in vivo, attenuates cartilage degradation caused by osteoarthritis (Deng et al, ). YAP/TAZ interact with TEA domain (TEAD) to suppress COX‐2 induction and modulate inflammatory responses (Zhang et al, ).…”

The Crosstalk Between Hippo-YAP Pathway and Innate Immunity

“…TRAF2 deficiency abolished TNFα-induced homo-dimerization and activation of MST1 (70,92). Similarly, MST1 and LATS1 were reported to be strongly activated by inflammatory cytokines, including TNFα and IL-1β, which further promoted YAP/TAZ degradation and attenuated the expression of YAP/TAZ-targeted genes (87). Interestingly, TAK1 involved in LATS1/2-independent YAP/TAZ degradation.…”

“…TRAF6 depletion alleviated the robust inflammatory response in endothelial YAP-deficient mice (86). Furthermore, Deng et al proved that YAP inhibited inflammatory responses mediated by NF-κB signaling in a murine model of experimental osteoarthritis (87). YAP overexpression disrupted the interaction between TAK1 and its downstream proteins IKKα and IKKβ, attenuating the activation of NF-κB signaling which played a major role in osteoarthritis pathogenesis via mediating the expression of proinflammatory cytokines such as TNFα (tumor necrosis factor α), IL-1β and IL-6 (88).…”

“…YAP overexpression disrupted the interaction between TAK1 and its downstream proteins IKKα and IKKβ, attenuating the activation of NF-κB signaling which played a major role in osteoarthritis pathogenesis via mediating the expression of proinflammatory cytokines such as TNFα (tumor necrosis factor α), IL-1β and IL-6 (88). Transgenic overexpression of YAP or genetic deletion of MST1/2 in mice alleviated osteoarthritis symptoms, whereas deletion of YAP in chondrocytes aggravated the progression of osteoarthritis (87). Additionally, in low-density-cells, YAP/TAZ translocates into the nuclei and forms YAP/TAZ-TEADs complex, functioning as a transcriptional activator.…”