Treating bone cancer pain (BCP) continues to be a clinical challenge, and the underlying mechanisms of BCP remain elusive. This study reports that Wnt5a/Ryk signaling in the dorsal root ganglion neurons is critical to the development of BCP. Tibia bone cavity tumor cell implantation produces spontaneous and evoked behaviorally expressed pain as well as ectopic sprouting and activity of Wnt5a/Ryk signaling in the neural soma and peripheral terminals and the tumor-affected bone tissues. Intraplantar, intratibial, or intrathecal injection of Wnt5a/Ryk signaling blockers significantly suppresses the painful symptoms. Peripheral injection of exogenous Wnt5a in naïve rats produces pain, and the dorsal root ganglion neurons become more sensitive to Wnt5a. Wnt5a/Ryk signaling activation increases intracellular calcium response and expression of transient receptors potential vanilloid type-1 and regulates capsaicin-induced intracellular calcium response. Blocking Ryk receptor activation suppresses Wnt5a-induced mechanical allodynia and thermal hyperalgesia. Wnt5a facilitation of transient receptors potential vanilloid type-1 sensitization is blocked by inhibiting c-Jun N-terminal kinase activation. These findings indicate a critical peripheral mechanism of Wnt5a/Ryk signaling underlying the pathogenesis of BCP and suggest that targeting Wnt5a/Ryk in the primary sensory neurons and the tumor-invasive area may be an effective approach for the prevention and treatment of BCP.

中文翻译：

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Wnt5a/Ryk 信号传导通过 JNK 介导的大鼠 TRPV1 通路使外周伤害感受器敏感，从而促进骨癌疼痛。


治疗骨癌疼痛 （BCP） 仍然是一项临床挑战，BCP 的潜在机制仍然难以捉摸。本研究报道，背根神经节神经元中的 Wnt5a/Ryk 信号转导对 BCP 的发育至关重要。胫骨骨腔肿瘤细胞植入产生自发性和诱发的行为表达疼痛，以及神经胞体和外周末梢以及受肿瘤累骨组织中 Wnt5a/Ryk 信号传导的异位发芽和活性。足底内、胫骨内或鞘内注射 Wnt5a/Ryk 信号阻滞剂可显着抑制疼痛症状。在幼稚大鼠中外周注射外源性 Wnt5a 会产生疼痛，背根神经节神经元对 Wnt5a 更加敏感。Wnt5a/Ryk 信号激活增加细胞内钙反应和瞬时受体潜在香草素 1 型的表达，并调节辣椒素诱导的细胞内钙反应。阻断 Ryk 受体激活抑制 Wnt5a 诱导的机械性异常性疼痛和热痛觉过敏。通过抑制 c-Jun N 末端激酶激活，阻断瞬时受体潜在香草素 1 型致敏的 Wnt5a 促进。这些发现表明 Wnt5a/Ryk 信号转导的关键外周机制是 BCP 发病机制的基础，并表明在初级感觉神经元和肿瘤浸润区域靶向 Wnt5a/Ryk 可能是预防和治疗 BCP 的有效方法。