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

• 成果类型: Article
• 署名作者: 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
• 署名单位: New York University; Yale University; Yale University; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Connecticut Healthcare System; Columbia University; New York University; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; New York University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5088
• DOI: 10.1038/s41586-023-06888-7
• 发表日期: 2024-01-18
• 关键词: sodium-channels; pain; activation; destabilization; contributes; expression; reveals; MODEL; mice

摘要

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 mu m(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 Ca2+ 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.