Role of the CXCR4/ALK5/Smad3 Signaling Pathway in Cancer-Induced Bone Pain

Chong Peng; Xue-Tai Chen; Heng Xu; Li-Ping Chen; Wen Shen

doi:10.2147/JPR.S260508

Role of the CXCR4/ALK5/Smad3 Signaling Pathway in Cancer-Induced Bone Pain

J Pain Res. 2020 Oct 14:13:2567-2576. doi: 10.2147/JPR.S260508. eCollection 2020.

Authors

Chong Peng^#¹, Xue-Tai Chen^#¹, Heng Xu², Li-Ping Chen², Wen Shen^{1

2}

Affiliations

¹ Jiangsu Province Key Laboratory of Anesthesiology and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, Jiangsu 221002, People's Republic of China.
² Department of Pain Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: The chemokine receptor, CXCR4, and the transforming growth factor-beta receptor, ALK5, both contribute to various processes associated with the sensation of pain. However, the relationship between CXCR4 and ALK5 and the possible mechanisms promoted by ALK5 in the development of pain have not been evaluated.

Materials and methods: Tumor cell implantation (TCI) technology was used to generate a model of cancer-induced bone pain (CIBP) in rats; intrathecal (i.t.) injections of small interfering (si) RNAs targeting CXCR4 and the ALK5-specific inhibitor, RepSox, were performed. Behavioral outcomes, Western blotting, and immunofluorescence techniques were used to evaluate the expression of the aforementioned specific target proteins in the CIBP model.

Results: The results revealed that i.t. administration of siRNAs targeting CXCR4 resulted in significant reductions in both mechanical and thermal hyperalgesia in rats with CIBP and likewise significantly reduced the expression of ALK5 in the spinal cord. Similarly, i.t. administration of RepSox also resulted in significant reductions in mechanical and thermal hyperalgesia in rats with CIBP together with diminished levels of spinal p-Smad3.

Conclusion: Taken together, our results suggest that CXCR4 expression in the spinal cord may be a critical mediator of CIBP via its capacity to activate ALK5 and downstream signaling pathways.

Keywords: cancer pain; chemokines; fluorescent antibody technique; neoplasms; sensation.

Grants and funding

This study was supported by the National Nature Science Foundation of China (81571066 to Wen Shen), the Key Project of the Natural Science Foundation of Jiangsu Education Department (16KJA320002 to Wen Shen).