Neuronal and Glial YAP/TAZ in the Spinal Cord Contribute to the Development of Bone Cancer Pain in Mice

The treatment of bone cancer pain (BCP) remains a major clinical challenge, and the mechanisms underlying BCP remain poorly understood. Here, we report that tumor cell implantation (TCI) led to nuclear accumulation of yes-associated protein (YAP) and transcriptional coactivator with PDZ (postsynaptic density protein 95, PSD-95; discs large, Dlg; zonula occludens-1, ZO-1)-binding motif (TAZ) and up-regulation of their mRNA (messenger ribonucleic acid) expression in Vglut2⁺ excitatory neurons, microglia, and astrocytes in the spinal dorsal horn. Pharmacological inhibition of YAP/TAZ or genetic knockout of YAP/TAZ in Vglut2⁺ excitatory neurons, microglia, or astrocytes significantly alleviates TCI-induced BCP. Mechanistically, ablation of YAP/TAZ in Vglut2⁺ excitatory neurons suppressed TCI-induced hyperexcitability of the dorsal horn neurons via β-catenin signaling modulation; concurrently, deletion of YAP/TAZ in microglia and astrocytes prevented TCI-induced activation of these glial cells and decreased levels of proinflammatory cytokines through regulation of nuclear factor kappa-B (NF-κB) signaling. The present study reveals the vital roles of spinal YAP/TAZ in the pathogenesis of BCP and identifies a potential molecular target for therapeutic intervention in BCP.