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bioRxiv · 10.1101/386698

Transcriptional regulation of voltage-gated sodium channels contributes to GM-CSF induced pain

Zhang, F.·Wang, Y.·Zhang, D.·Fan, X.·Han, H.·Du, X.·Gamper, N.·Zhang, H.
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Abstract

Granolocyte-macrophage colony stimulating factor (GM-CSF) induces 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. Rats implanted with bone cancer cells develop mechanical and thermal hyperalgesia but antagonizing GM-CSF in these animals significantly reduced such hypersensitivity. Nociceptor-specific voltage gated Na+ channels Nav1.7, Nav1.8 and Nav1.9 were found to be selectively up-regulated in rat DRG neurons treated with GM-CSF, which resulted in enhanced excitability. GM-CSF activated the Jak2 and Stat3 signaling pathway which promoted the transcription of Nav1.7-1.9 in DRG neurons. Accordingly targeted knocking down either Nav1.7-1.9 or Jak2/Stat3 in DRG neurons alleviated the hyperalgesia in rats. Our findings describe a new bone cancer pain mechanism and provide a new insight into the physiological and pathological functions of GM-CSF.

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Zhang, F., Wang, Y., Zhang, D., Fan, X., Han, H., Du, X., Gamper, N., Zhang, H.. 2018-08-07. Transcriptional regulation of voltage-gated sodium channels contributes to GM-CSF induced pain. https://doi.org/10.1101/386698

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