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.
Authors
Shouan Zhu, Jianxi Zhu, Gehua Zhen, Yihe Hu, Senbo An, Yusheng Li, Qin Zheng, Zhiyong Chen, Ya Yang, Mei Wan, Richard Leroy Skolasky, Yong Cao, Tianding Wu, Bo Gao, Mi Yang, Manman Gao, Julia Kuliwaba, Shuangfei Ni, Lei Wang, Chuanlong Wu, David Findlay, Holger K. Eltzschig, Hong Wei Ouyang, Janet Crane, Feng-Quan Zhou, Yun Guan, Xinzhong Dong, Xu Cao
Figure 4
Netrin-1 from osteoclasts induces axonal growth.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)