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

• Published in: Nature (London) Vol. 625; no. 7995; pp. 557 - 565
• Main Authors: Fu, Wenyu, Vasylyev, Dmytro, Bi, Yufei, Zhang, Mingshuang, Sun, Guodong, Khleborodova, Asya, Huang, Guiwu, Zhao, Libo, Zhou, Renpeng, Li, Yonggang, Liu, Shujun, Cai, Xianyi, He, Wenjun, Cui, Min, Zhao, Xiangli, Hettinghouse, Aubryanna, Good, Julia, Kim, Ellen, Strauss, Eric, Leucht, Philipp, Schwarzkopf, Ran, Guo, Edward X., Samuels, Jonathan, Hu, Wenhuo, Attur, Mukundan, Waxman, Stephen G., Liu, Chuan-ju
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18-01-2024; Nature Publishing Group
• Subjects: 631/208/200; 692/699/1670/407; Ablation; Animal models; Arthritis; Calcium (intracellular); Calcium ions; Calcium signalling; Cartilage; Channel gating; Channels; Chondrocytes; Degeneration; Dorsal root ganglia; Ganglia; Humanities and Social Sciences; Intracellular signalling; Joint diseases; multidisciplinary; Osteoarthritis; Pain; Science; Science (multidisciplinary); Secretome; Sodium; Sodium channels (voltage-gated); Therapeutic targets
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-023-06888-7

Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain
1
. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes
2
, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Na
v
1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Na
v
1.7 channels, with a density of 0.1 to 0.15 channels per µm
2
and 350 to 525 channels per cell. Serial genetic ablation of Na
v
1.7 in multiple mouse models demonstrates that Na
v
1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Na
v
1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Na
v
1.7 with selective or clinically used pan-Na
v
channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Na
v
1.7 blockers regulate intracellular Ca
2+
signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Na
v
1.7 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.
The voltage-gated sodium channel Na
v
1.7 has a dual role in osteoarthritis—in chondrocytes, it promotes joint damage, and in dorsal root ganglia neurons, it increases pain transmission.