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

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 ϩ 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.

Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channels

“…In neocortical neurons, G-protein activation hyperpolarized VGSC gating and this was blocked by GDPβS ( Mattheisen et al, 2018 ) which is inconsistent with the effect we observed here. Other possible explanations are that CaSR could regulate VGSC subunit expression or post translational modification ( Cantrell et al, 1996 ; Zhang et al, 2019 ), and this may represent a compensatory mechanism similar to that observed with other mutant mouse models ( Jun et al, 1999 ). Loss of CaSR also hyperpolarized the neocortical neurons ( Figure 1I ) and this may have been due to decreased function of depolarizing components or stimulation of hyperpolarizing elements.…”

Frataxin gene editing rescues Friedreich’s ataxia pathology in dorsal root ganglia organoid-derived sensory neurons

“…To further confirm the peripheral sensory identity of the neurons, we proceeded with candidate gene expression analysis, revealing a strong upregulation of several peripheral sensory neuronal markers, including POU4F1, GFRA2 , P2RX3 , PTPRT, NRG1 , vGLUT1 , and sodium channel genes (Supplementary Fig. 3e ) 41 . Likewise, βIII-Tubulin, PRPH, and NF200, a type IV intermediate filament associated with high caliber neurites, were clearly observed within the axonal projections (Supplementary Figs.…”

Granulocyte-Macrophage Colony Stimulating Factor As an Indirect Mediator of Nociceptor Activation and Pain

“…Previous studies have suggested that GM-CSF can act on and stimulate sensory neurons. Bali et al (2013) suggested that GM-CSF brought about transcriptional regulation of several pain genes in sensory neurons in a model of cancer pain, an observation replicated by Schweizerhof et al (2009) and Zhang et al (2019). Donatien et al, 2018 report that GM-CSF can enhance capsaicin-induced calcium influx in DRG neurons, although not directly induce calcium influx.…”