Neuronal and Glial YAP/TAZ in the Spinal Cord Contribute to the Development of Bone Cancer Pain in Mice
Bo Peng1,2 · Xiaqing Lin1,2 · Jiang‑Jian Hu1,2 · Huabao Liao1,2 · Cheng Li1,2 · Zhaoyu Li3 · Xue‑Jun Song1,2
1 Department of Medical Neuroscience, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
2 SUSTech Center for Pain Medicine, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
3 Queensland Brain Institute, The University of Queensland, Brisbane 4072, Australia
Abstract
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.
Keywords
β-catenin; NF-κB; Vglut2+ excitatory neurons; Microglia; Astrocytes; TNF-α; IL-1β; IL-6
