Activation of the BMP2-SMAD1-CGRP pathway in dorsal root ganglia contributes to bone cancer pain in a rat model

Wei Wang; Zhihao Gong; Kai Wang; Mi Tian; Yuxin Zhang; Xin Li; Xingji You; Jingxiang Wu

doi:10.1016/j.heliyon.2024.e27350

Activation of the BMP2-SMAD1-CGRP pathway in dorsal root ganglia contributes to bone cancer pain in a rat model

Heliyon. 2024 Mar 4;10(6):e27350. doi: 10.1016/j.heliyon.2024.e27350. eCollection 2024 Mar 30.

Authors

Wei Wang¹, Zhihao Gong¹, Kai Wang², Mi Tian³, Yuxin Zhang¹, Xin Li⁴, Xingji You⁴, Jingxiang Wu¹

Affiliations

¹ Department of Anesthesiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200030, China.
² Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200030, China.
³ Department of Intensive Care Medicine, HuaShan Hospital, Fudan University, Shanghai 200040, China.
⁴ School of Medicine, Shanghai University, Shanghai 200444, China.

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 (CGRP_8-37). 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.

Keywords: BMP2; Bone cancer pain; CGRP; Dorsal root ganglia; Peripheral sensitization.