Transcriptional Regulation of Voltage-Gated Sodium Channels Contributes to GM-CSF-Induced Pain

Zhang, F; Wang, YY; Liu, Y; Han, H; Zhang, DD; Fan, XZZ; Du, XN; Gamper, N; Zhang, HL

Zhang, HL (reprint author), Hebei Med Univ, Minist Educ, Dept Pharmacol, Shijiazhuang 050017, Hebei, Peoples R China.; Zhang, HL (reprint author), Hebei Med Univ, Minist Educ, Key Lab Neural & Vasc Biol, Shijiazhuang 050017, Hebei, Peoples R China.; Zhang

JOURNAL OF NEUROSCIENCE, 2019; 39 (26): 5222

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces the production of granulocyte and macrophage populations from the hematopoietic progenitor cells; it is one of the most common growth factors in the blood. GM-CSF is also involved in bone cancer pain development by regulating tumor-nerve interactions, remodeling of peripheral nerves, and sensitization of damage-sensing (nociceptive) nerves. However, the precise mechanism for GM-CSF-dependent pain is unclear. In this study, we found that GM-CSF is highly expressed in human malignant osteosarcoma. Female Sprague Dawley rats implanted with bone cancer cells develop mechanical and thermal hyperalgesia, but antagonizing GM-CSF in these animals significantly reduced such hypersensitivity. The voltage-gated Na+ channels Nav1.7, Nav1.8, and Nav1.9 were found to be selectively upregulated in rat DRG neurons treated with GM-CSF, which resulted in enhanced excitability. GM-CSF activated the Janus kinase 2 (Jak2)-signal transducer and activator of transcription protein 3 (Stat3) signaling pathway, which promoted the transcription of Nav1.7-1.9 in DRG neurons. Accordingly, targeted knocking down of either Nav1.7-1.9 or Jak2/Stat3 in DRG neurons in vivo alleviated the hyperalgesia in male Sprague Dawley rats. Our findings describe a novel bone cancer pain mechanism and provide a new insight into the physiological and pathological functions of GM-CSF.

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