Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain

作者：Shouan Zhu, Jianxi Zhu, Gehua Zhen, Yihe Hu, Senbo An, Yusheng Li, Zheng Qin, Zhiyong Chen, Ya Feng Yang, Mei Wan, Richard L. Skolasky, Yong Bing Cao, Tianding Wu, Bo Gao, Mi Yang, Manman Gao, Julia S. Kuliwaba, Shuangfei Ni, Lei Wang, Chuanlong Wu, David M. Findlay, Holger K. Eltzschig, Hong Wei Ouyang, Janet L. Crane, Feng‐Quan Zhou, Yun Guan, Xinzhong Dong, Xu Cao · 发表于：Journal of Clinical Investigation · 年份：2018 · DOI：10.1172/jci121561 · 被引用次数：467 · 研究领域：Axon Guidance and Neuronal Signaling、Bone Metabolism and Diseases、Wnt/β-catenin signaling in development and cancer

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.