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Papers of the Week

Papers: 20 Apr 2019 - 26 Apr 2019

Animal Studies

2019 Jun 26

J Neurosci



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


Zhang F, Wang Y, Liu Y, Han H, Zhang D, Fan X, Du X, Gamper N, Zhang H
J Neurosci. 2019 Jun 26; 39(26):5222-5233.
PMID: 31015342.


Granulocyte-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. 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 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 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.It has been reported that GM-CSF plays a key role in bone cancer pain, yet the underlying mechanisms involved in GM-CSF-mediated signaling pathway in nociceptors is not fully understood. Here, we showed that GM-CSF promotes bone cancer-associated pain by enhancing excitability of DRG neurons via the Jak2-Stat3-mediated upregulation of expression of nociceptor-specific voltage-gated sodium channels. Our study provides a detailed understanding of the roles that sodium channels and Jak2/Stat3 pathway play in the GM-CSF-mediated bone cancer pain; our data also highlight the therapeutic potential of targeting GM-CSF.