Na(v)1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis Journal Article
| Authors: | Fu, W.; Vasylyev, D.; Bi, Y.; Zhang, M.; Sun, G.; Khleborodova, A.; Huang, G.; Zhao, L.; Zhou, R.; Li, Y.; Liu, S.; Cai, X.; He, W.; Cui, M.; Zhao, X.; Hettinghouse, A.; Good, J.; Kim, E.; Strauss, E.; Leucht, P.; Schwarzkopf, R.; Guo, E. X.; Samuels, J.; Hu, W.; Attur, M.; Waxman, S. G.; Liu, C. J. |
| Article Title: | Na(v)1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis |
| Abstract: | 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 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. © 2024, The Author(s). |
| Keywords: | signal transduction; adult; controlled study; human tissue; protein expression; human cell; genetics; disease course; nonhuman; protein function; animal cell; mouse; animal; metabolism; animals; mice; animal tissue; enzyme inhibition; pain; gene expression; animal experiment; animal model; calcium; enzyme regulation; messenger rna; protein secretion; real time polymerase chain reaction; upregulation; osteoarthritis; heat shock protein 70; ex vivo study; sodium; electrophysiology; calcium cell level; knee osteoarthritis; disease; cell; spinal ganglion; ganglia, spinal; calcium signaling; chondrocyte; chondrocytes; humans; human; male; female; article; rna sequencing; ic50; sodium channel nav1.7; nav1.7 voltage-gated sodium channel; sodium channel blockers; sodium channel blocking agent |
| Journal Title: | Nature |
| Volume: | 625 |
| Issue: | 7995 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-01-18 |
| Start Page: | 557 |
| End Page: | 565 |
| Language: | English |
| DOI: | 10.1038/s41586-023-06888-7 |
| PUBMED: | 38172636 |
| PROVIDER: | scopus |
| PMCID: | PMC10794151 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
