Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain

Shouan Zhu, Jianxi Zhu, Gehua Zhen, Yihe Hu, Senbo An, Yusheng Li, Qin Zheng, Zhiyong Chen, Ya Yang, Mei Wan, Richard Skolasky, Yong Cao, Tianding Wu, Bo Gao, Mi Yang, Manman Gao, Julia Kuliwaba, Shuangfei Ni, Lei Wang, Chuanlong WuDavid Findlay, Holger K. Eltzschig, Hong Wei Ouyang, Janet Crane, Fengquan Zhou, Yun Guan, Xinzhong Dong, Xu Cao

Research output: Contribution to journalArticle

Abstract

Joint pain is the defining symptom of osteoarthritis (OA) but its origin and mechanisms remain unclear. Here, we investigated an unprecedented role of osteoclast-initiated subchondral bone remodeling in sensory innervation for OA pain. We show that osteoclasts secrete netrin-1 to induce sensory nerve axonal growth in subchondral bone. Reduction of osteoclast formation by knockout of receptor activator of nuclear factor kappa-B ligand (Rankl) in osteocytes inhibited the growth of sensory nerves into subchondral bone, dorsal root ganglion neuron hyperexcitability, and behavioral measures of pain hypersensitivity in OA mice. Moreover, we demonstrated a possible role for netrin-1 secreted by osteoclasts during aberrant subchondral bone remodeling in inducing sensory innervation and OA pain through its receptor DCC (deleted in colorectal cancer). Importantly, knockout of Netrin1 in tartrate-resistant acid phosphatase–positive (TRAP-positive) osteoclasts or knockdown of Dcc reduces OA pain behavior. In particular, inhibition of osteoclast activity by alendronate modifies aberrant subchondral bone remodeling and reduces innervation and pain behavior at the early stage of OA. These results suggest that intervention of the axonal guidance molecules (e.g., netrin-1) derived from aberrant subchondral bone remodeling may have therapeutic potential for OA pain.

Original languageEnglish (US)
Pages (from-to)1076-1093
Number of pages18
JournalJournal of Clinical Investigation
Volume129
Issue number3
DOIs
StatePublished - Mar 1 2019

Fingerprint

Osteoclasts
Osteoarthritis
Bone Remodeling
Bone and Bones
Pain
RANK Ligand
Alendronate
Osteocytes
Arthralgia
Spinal Ganglia
Growth
Colorectal Neoplasms
Hypersensitivity
Neurons
Acids
netrin-1

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain. / Zhu, Shouan; Zhu, Jianxi; Zhen, Gehua; Hu, Yihe; An, Senbo; Li, Yusheng; Zheng, Qin; Chen, Zhiyong; Yang, Ya; Wan, Mei; Skolasky, Richard; Cao, Yong; Wu, Tianding; Gao, Bo; Yang, Mi; Gao, Manman; Kuliwaba, Julia; Ni, Shuangfei; Wang, Lei; Wu, Chuanlong; Findlay, David; Eltzschig, Holger K.; Ouyang, Hong Wei; Crane, Janet; Zhou, Fengquan; Guan, Yun; Dong, Xinzhong; Cao, Xu.

In: Journal of Clinical Investigation, Vol. 129, No. 3, 01.03.2019, p. 1076-1093.

Research output: Contribution to journalArticle

Zhu, S, Zhu, J, Zhen, G, Hu, Y, An, S, Li, Y, Zheng, Q, Chen, Z, Yang, Y, Wan, M, Skolasky, R, Cao, Y, Wu, T, Gao, B, Yang, M, Gao, M, Kuliwaba, J, Ni, S, Wang, L, Wu, C, Findlay, D, Eltzschig, HK, Ouyang, HW, Crane, J, Zhou, F, Guan, Y, Dong, X & Cao, X 2019, 'Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain', Journal of Clinical Investigation, vol. 129, no. 3, pp. 1076-1093. https://doi.org/10.1172/JCI121561
Zhu, Shouan ; Zhu, Jianxi ; Zhen, Gehua ; Hu, Yihe ; An, Senbo ; Li, Yusheng ; Zheng, Qin ; Chen, Zhiyong ; Yang, Ya ; Wan, Mei ; Skolasky, Richard ; Cao, Yong ; Wu, Tianding ; Gao, Bo ; Yang, Mi ; Gao, Manman ; Kuliwaba, Julia ; Ni, Shuangfei ; Wang, Lei ; Wu, Chuanlong ; Findlay, David ; Eltzschig, Holger K. ; Ouyang, Hong Wei ; Crane, Janet ; Zhou, Fengquan ; Guan, Yun ; Dong, Xinzhong ; Cao, Xu. / Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 3. pp. 1076-1093.
@article{6a1489beb62e4aa2ada7aff86047e093,
title = "Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain",
abstract = "Joint pain is the defining symptom of osteoarthritis (OA) but its origin and mechanisms remain unclear. Here, we investigated an unprecedented role of osteoclast-initiated subchondral bone remodeling in sensory innervation for OA pain. We show that osteoclasts secrete netrin-1 to induce sensory nerve axonal growth in subchondral bone. Reduction of osteoclast formation by knockout of receptor activator of nuclear factor kappa-B ligand (Rankl) in osteocytes inhibited the growth of sensory nerves into subchondral bone, dorsal root ganglion neuron hyperexcitability, and behavioral measures of pain hypersensitivity in OA mice. Moreover, we demonstrated a possible role for netrin-1 secreted by osteoclasts during aberrant subchondral bone remodeling in inducing sensory innervation and OA pain through its receptor DCC (deleted in colorectal cancer). Importantly, knockout of Netrin1 in tartrate-resistant acid phosphatase–positive (TRAP-positive) osteoclasts or knockdown of Dcc reduces OA pain behavior. In particular, inhibition of osteoclast activity by alendronate modifies aberrant subchondral bone remodeling and reduces innervation and pain behavior at the early stage of OA. These results suggest that intervention of the axonal guidance molecules (e.g., netrin-1) derived from aberrant subchondral bone remodeling may have therapeutic potential for OA pain.",
author = "Shouan Zhu and Jianxi Zhu and Gehua Zhen and Yihe Hu and Senbo An and Yusheng Li and Qin Zheng and Zhiyong Chen and Ya Yang and Mei Wan and Richard Skolasky and Yong Cao and Tianding Wu and Bo Gao and Mi Yang and Manman Gao and Julia Kuliwaba and Shuangfei Ni and Lei Wang and Chuanlong Wu and David Findlay and Eltzschig, {Holger K.} and Ouyang, {Hong Wei} and Janet Crane and Fengquan Zhou and Yun Guan and Xinzhong Dong and Xu Cao",
year = "2019",
month = "3",
day = "1",
doi = "10.1172/JCI121561",
language = "English (US)",
volume = "129",
pages = "1076--1093",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "3",

}

TY - JOUR

T1 - Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain

AU - Zhu, Shouan

AU - Zhu, Jianxi

AU - Zhen, Gehua

AU - Hu, Yihe

AU - An, Senbo

AU - Li, Yusheng

AU - Zheng, Qin

AU - Chen, Zhiyong

AU - Yang, Ya

AU - Wan, Mei

AU - Skolasky, Richard

AU - Cao, Yong

AU - Wu, Tianding

AU - Gao, Bo

AU - Yang, Mi

AU - Gao, Manman

AU - Kuliwaba, Julia

AU - Ni, Shuangfei

AU - Wang, Lei

AU - Wu, Chuanlong

AU - Findlay, David

AU - Eltzschig, Holger K.

AU - Ouyang, Hong Wei

AU - Crane, Janet

AU - Zhou, Fengquan

AU - Guan, Yun

AU - Dong, Xinzhong

AU - Cao, Xu

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Joint pain is the defining symptom of osteoarthritis (OA) but its origin and mechanisms remain unclear. Here, we investigated an unprecedented role of osteoclast-initiated subchondral bone remodeling in sensory innervation for OA pain. We show that osteoclasts secrete netrin-1 to induce sensory nerve axonal growth in subchondral bone. Reduction of osteoclast formation by knockout of receptor activator of nuclear factor kappa-B ligand (Rankl) in osteocytes inhibited the growth of sensory nerves into subchondral bone, dorsal root ganglion neuron hyperexcitability, and behavioral measures of pain hypersensitivity in OA mice. Moreover, we demonstrated a possible role for netrin-1 secreted by osteoclasts during aberrant subchondral bone remodeling in inducing sensory innervation and OA pain through its receptor DCC (deleted in colorectal cancer). Importantly, knockout of Netrin1 in tartrate-resistant acid phosphatase–positive (TRAP-positive) osteoclasts or knockdown of Dcc reduces OA pain behavior. In particular, inhibition of osteoclast activity by alendronate modifies aberrant subchondral bone remodeling and reduces innervation and pain behavior at the early stage of OA. These results suggest that intervention of the axonal guidance molecules (e.g., netrin-1) derived from aberrant subchondral bone remodeling may have therapeutic potential for OA pain.

AB - Joint pain is the defining symptom of osteoarthritis (OA) but its origin and mechanisms remain unclear. Here, we investigated an unprecedented role of osteoclast-initiated subchondral bone remodeling in sensory innervation for OA pain. We show that osteoclasts secrete netrin-1 to induce sensory nerve axonal growth in subchondral bone. Reduction of osteoclast formation by knockout of receptor activator of nuclear factor kappa-B ligand (Rankl) in osteocytes inhibited the growth of sensory nerves into subchondral bone, dorsal root ganglion neuron hyperexcitability, and behavioral measures of pain hypersensitivity in OA mice. Moreover, we demonstrated a possible role for netrin-1 secreted by osteoclasts during aberrant subchondral bone remodeling in inducing sensory innervation and OA pain through its receptor DCC (deleted in colorectal cancer). Importantly, knockout of Netrin1 in tartrate-resistant acid phosphatase–positive (TRAP-positive) osteoclasts or knockdown of Dcc reduces OA pain behavior. In particular, inhibition of osteoclast activity by alendronate modifies aberrant subchondral bone remodeling and reduces innervation and pain behavior at the early stage of OA. These results suggest that intervention of the axonal guidance molecules (e.g., netrin-1) derived from aberrant subchondral bone remodeling may have therapeutic potential for OA pain.

UR - http://www.scopus.com/inward/record.url?scp=85062424454&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062424454&partnerID=8YFLogxK

U2 - 10.1172/JCI121561

DO - 10.1172/JCI121561

M3 - Article

C2 - 30530994

AN - SCOPUS:85062424454

VL - 129

SP - 1076

EP - 1093

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 3

ER -