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

• Published in: Nature communications Vol. 10; no. 1; pp. 5643 - 15
• Main Authors: Ni, Shuangfei, Ling, Zemin, Wang, Xiao, Cao, Yong, Wu, Tianding, Deng, Ruoxian, Crane, Janet L., Skolasky, Richard, Demehri, Shadpour, Zhen, Gehua, Jain, Amit, Wu, Panfeng, Pan, Dayu, Hu, Bo, Lyu, Xiao, Li, Yusheng, Chen, Hao, Qi, Huabin, Guan, Yun, Dong, Xinzhong, Wan, Mei, Zou, Xuenong, Lu, Hongbin, Hu, Jianzhong, Cao, Xu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.12.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/51; 13/89; 14; 14/19; 38; 38/88; 631/378/1689/2610; 631/443/63; Aging; Aging - pathology; Animals; Back surgery; Behavior, Animal; Biomedical materials; Dinoprostone; Disease Models, Animal; Humanities and Social Sciences; Humans; Hyperalgesia - pathology; Hypersensitivity; Hypersensitivity - pathology; Innervation; Lumbar Vertebrae - pathology; Magnetic resonance imaging; Male; Medicine; Mice, Inbred C57BL; Mice, Knockout; Motor Endplate - pathology; multidisciplinary; Netrin-1; Netrin-1 - deficiency; Netrin-1 - metabolism; Osteoclasts; Osteoclasts - metabolism; Pain; Pain - pathology; Porosity; Prostaglandin E2; Science; Science (multidisciplinary); Sensory Receptor Cells - metabolism; Signal Transduction; Sodium; Spine; Spine - pathology; Vertebrae
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13476-9

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 Na v 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. Spinal pain is a major clinical problem. Here the authors show that osteoclasts create porous area of endplates of the vertebrae and sensory innervation of porous endplates by Netrin-1 release from osteoclasts mediates PGE2-induced spinal hypersensitivity in mice.