PDF(Pubmed)
Abstract：
Peripheral nerve remodeling and sensitization are involved in cancer-related bone pain. As a member of the transforming growth factor-β class, bone morphogenetic protein 2 (BMP2) is recognized to have a role in the development of the neurological and skeletal systems. Our previous work showed that BMP2 is critical for bone cancer pain (BCP) sensitization. However, the mechanism remains unknown. In the current study, we demonstrated a substantial increase in BMP2 expression in the dorsal root ganglia (DRG) in a rat model of BCP. Knockdown of BMP2 expression ameliorated BCP in rats. Furthermore, the DRG neurons of rats with BCP expressed higher levels of calcitonin gene-related peptide (CGRP), and BCP was successfully suppressed by intrathecal injection of a CGRP receptor blocker (CGRP8-37). Downregulation of BMP2 expression reduced the expression of CGRP in the DRG of rats with BCP and relieved pain behavior. Moreover, we revealed that upregulation of CGRP expression in the DRG may be induced by activation of the BMPR/Smad1 signaling pathway. These findings suggest that BMP2 contributes to BCP by upregulating CGRP in DRG neurons via activating BMPR/Smad1 signaling pathway and that therapeutic targeting of the BMP2-Smad1-CGRP pathway may ameliorate BCP in the context of advanced cancer.
摘要：
周围神经重塑和致敏与癌症相关的骨痛有关。作为转化生长因子-β类的成员，骨形态发生蛋白2（BMP2）被认为在神经和骨骼系统的发育中起作用。我们先前的工作表明，BMP2对骨癌疼痛（BCP）致敏至关重要。然而,机制仍然未知。在目前的研究中,在BCP的大鼠模型中，我们证明了背根神经节（DRG）中BMP2的表达显着增加。敲除BMP2的表达改善了大鼠的BCP。此外，BCP大鼠DRG神经元表达较高水平的降钙素基因相关肽(CGRP),鞘内注射CGRP受体阻滞剂（CGRP8-37）成功抑制了BCP。BMP2表达下调可降低BCP大鼠DRG中CGRP的表达，缓解疼痛行为。此外，我们发现，DRG中CGRP表达的上调可能是由BMPR/Smad1信号通路的激活引起的。这些发现表明，BMP2通过激活BMPR/Smad1信号通路上调DRG神经元中的CGRP来促进BCP，并且BMP2-Smad1-CGRP通路的治疗性靶向可能在晚期癌症的背景下改善BCP。
