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 Skolasky, Shadpour Demehri, Gehua Zhen, Amit Jain, Panfeng Wu, Dayu Pan, Bo Hu, Xiao Lyu, Yusheng Li, Hao Chen, Huabin Qi, Yun Guan, Xinzhong Dong, Mei Wan, Xuenong Zou, Hongbin Lu, Jianzhong Hu () and Xu Cao ()
Additional contact information
Shuangfei Ni: The Johns Hopkins University School of Medicine
Zemin Ling: The Johns Hopkins University School of Medicine
Xiao Wang: The Johns Hopkins University School of Medicine
Yong Cao: The Johns Hopkins University School of Medicine
Tianding Wu: The Johns Hopkins University School of Medicine
Ruoxian Deng: The Johns Hopkins University School of Medicine
Janet L. Crane: The Johns Hopkins University School of Medicine
Richard Skolasky: The Johns Hopkins University School of Medicine
Shadpour Demehri: The Johns Hopkins University School of Medicine
Gehua Zhen: The Johns Hopkins University School of Medicine
Amit Jain: The Johns Hopkins University School of Medicine
Panfeng Wu: The Johns Hopkins University School of Medicine
Dayu Pan: The Johns Hopkins University School of Medicine
Bo Hu: The Johns Hopkins University School of Medicine
Xiao Lyu: The Johns Hopkins University School of Medicine
Yusheng Li: The Johns Hopkins University School of Medicine
Hao Chen: The Johns Hopkins University School of Medicine
Huabin Qi: The Johns Hopkins University School of Medicine
Yun Guan: The Johns Hopkins University School of Medicine
Xinzhong Dong: The Johns Hopkins University School of Medicine, Howard Hughes Medical Institute
Mei Wan: The Johns Hopkins University School of Medicine
Xuenong Zou: The First Affiliated Hospital of Sun Yat-sen University
Hongbin Lu: Central South University
Jianzhong Hu: Central South University
Xu Cao: The Johns Hopkins University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13476-9

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