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<p>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<sup>+</sup> excitatory neurons, microglia, and astrocytes in the spinal dorsal horn. Pharmacological inhibition of YAP/TAZ or genetic knockout of YAP/TAZ in Vglut2<sup>+</sup> excitatory neurons, microglia, or astrocytes significantly alleviates TCI-induced BCP. Mechanistically, ablation of YAP/TAZ in Vglut2<sup>+</sup> excitatory neurons suppressed TCI-induced hyperexcitability of the dorsal horn neurons <i>via</i> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年3月22日

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  • Bo Peng,
  • Xiaqing Lin,
  • Jiang-Jian Hu,
  • Huabao Liao,
  • Cheng Li,
  • Zhaoyu Li,
  • Xue-Jun Song

摘要

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.