Na1.7 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 pain. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Na1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Na1.7 channels, with a density of 0.1 to 0.15 channels per µm and 350 to 525 channels per cell. Serial genetic ablation of Na1.7 in multiple mouse models demonstrates that Na1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Na1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Na1.7 with selective or clinically used pan-Na channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Na1.7 blockers regulate intracellular Ca signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Na1.7 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.