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J Clin Invest. 2019 Mar 1;129(3):1076-1093. doi: 10.1172/JCI121561. Epub 2019 Feb 4.

Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain.

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Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China.
Department of Orthopaedic Surgery, Xiangya Hospital, Central South University, Changsha, China.
Department of Neuroscience, Neurosurgery, and Dermatology, Center of Sensory Biology, Johns Hopkins University School of Medicine, Howard Hughes Medical Institute, Baltimore, Maryland, USA.
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Department of Orthopaedics and Trauma, Royal Adelaide Hospital, University of Adelaide, Adelaide, Australia.
Department of Anesthesiology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas, USA.
ZJU-UoE Joint Institute, School of Medicine, Zhejiang University, Hangzhou, China.


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.


Bone Biology; Innervation; Neuroscience; Osteoarthritis; Pain

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