Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis

Wenyu Fu, Dmytro Vasylyev, Yufei Bi, Mingshuang Zhang, Guodong Sun, Asya Khleborodova, Guiwu Huang, Libo Zhao, Renpeng Zhou, Yonggang Li, Shujun Liu, Xianyi Cai, Wenjun He, Min Cui, Xiangli Zhao, Aubryanna Hettinghouse, Julia Good, Ellen Kim, Eric Strauss, Philipp Leucht, Ran Schwarzkopf, Edward X. Guo, Jonathan Samuels, Wenhuo Hu, Mukundan Attur, Stephen G. Waxman () and Chuan-ju Liu ()
Additional contact information
Wenyu Fu: New York University Grossman School of Medicine
Dmytro Vasylyev: Yale School of Medicine
Yufei Bi: New York University Grossman School of Medicine
Mingshuang Zhang: New York University Grossman School of Medicine
Guodong Sun: New York University Grossman School of Medicine
Asya Khleborodova: New York University Grossman School of Medicine
Guiwu Huang: New York University Grossman School of Medicine
Libo Zhao: New York University Grossman School of Medicine
Renpeng Zhou: New York University Grossman School of Medicine
Yonggang Li: New York University Grossman School of Medicine
Shujun Liu: Yale School of Medicine
Xianyi Cai: New York University Grossman School of Medicine
Wenjun He: New York University Grossman School of Medicine
Min Cui: New York University Grossman School of Medicine
Xiangli Zhao: New York University Grossman School of Medicine
Aubryanna Hettinghouse: New York University Grossman School of Medicine
Julia Good: New York University Grossman School of Medicine
Ellen Kim: New York University Grossman School of Medicine
Eric Strauss: New York University Grossman School of Medicine
Philipp Leucht: New York University Grossman School of Medicine
Ran Schwarzkopf: New York University Grossman School of Medicine
Edward X. Guo: Columbia University
Jonathan Samuels: New York University Grossman School of Medicine
Wenhuo Hu: Memorial Sloan Kettering Cancer Center
Mukundan Attur: New York University Grossman School of Medicine
Stephen G. Waxman: Yale School of Medicine
Chuan-ju Liu: New York University Grossman School of Medicine

Nature, 2024, vol. 625, issue 7995, 557-565

Abstract: Abstract Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.

Date: 2024
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DOI: 10.1038/s41586-023-06888-7

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