Nav1.7 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 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.