Na v 1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis.

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 Nav 1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav 1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav 1.7 in multiple mouse models demonstrates that Nav 1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav 1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav 1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav 1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav 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.