Zhang, F, Wang, Y, Liu, Y et al. (6 more authors) (2019) Transcriptional Regulation of Voltage-Gated Sodium Channels Contributes to GM-CSF-Induced Pain. Journal of Neuroscience, 39 (26). pp. 5222-5233. ISSN 1529-2401
Abstract
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.
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Copyright, Publisher and Additional Information: | (c) 2019 the authors. This is an author produced version of a paper published in the Journal of Neuroscience. Uploaded in accordance with the publisher's self-archiving policy. | ||||||
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Institution: | The University of Leeds | ||||||
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) | ||||||
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Depositing User: | Symplectic Publications | ||||||
Date Deposited: | 26 Apr 2019 15:05 | ||||||
Last Modified: | 23 Oct 2019 00:39 | ||||||
Status: | Published | ||||||
Publisher: | Society for Neuroscience | ||||||
Identification Number: | https://doi.org/10.1523/JNEUROSCI.2204-18.2019 |