Sensory innervation in porous endplates by Netrin-1 from osteoclasts mediates PGE2-induced spinal hypersensitivity in mice

Shuangfei Ni, Zemin Ling, Xiao Wang, Yong Cao, Tianding Wu, Ruoxian Deng, Janet L. Crane, Richard Skolask, Shadpour Demehril, Gehua Zhen, Amit Jain, Panfeng Wu, Dayu Pan, Bo Hu, Xiao Lyu, Yusheng Li, Hao Chen, Huabin Qi, Yun Guan, Xinzhong DongMei Wan, Xuenong Zou, Hongbin Lu, Jianzhong Hu, Xu Cao

Research output: Contribution to journalArticlepeer-review

Abstract

Spinal pain is a major clinical problem, however, its origins and underlying mechanisms remain unclear. Here we report that in mice, osteoclasts induce sensory innervation in the porous endplates which contributes to spinal hypersensitivity in mice. Sensory innervation of the porous areas of sclerotic endplates in mice was confirmed. Lumbar spine instability (LSI), or aging, induces spinal hypersensitivity in mice. In these conditions, we show that there are elevated levels of PGE2 which activate sensory nerves, leading to sodium influx through Nav 1.8 channels. We show that knockout of PGE2 receptor 4 in sensory nerves significantly reduces spinal hypersensitivity. Inhibition of osteoclast formation by knockout Rankl in the osteocytes significantly inhibits LSI-induced porosity of endplates, sensory innervation, and spinal hypersensitivity. Knockout of Netrin-1 in osteoclasts abrogates sensory innervation into porous endplates and spinal hypersensitivity. These findings suggest that osteoclast-initiated porosity of endplates and sensory innervation are potential therapeutic targets for spinal pain.

Original languageEnglish (US)
Article number5643
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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