Targeting Macrophage Connexin 43 Hemichannels Suppresses Synovial Inflammation and Osteoarthritis

Osteoarthritis (OA) is the most common chronic joint disease, yet no disease-modifying therapies exist. Synovial inflammation is increasingly recognized as a key driver of OA progression, but its therapeutic targets remain poorly defined. Here we show that selective inhibition of connexin 43 (Cx43) hemichannels (HCs) attenuates OA progression in a murine post-traumatic OA model. AAV-mediated Cx43 deletion reduced cartilage degeneration, synovial inflammation, subchondral bone sclerosis, and pain. We developed a monoclonal antibody, Cx43(M1), that selectively blocks Cx43 HCs without disrupting gap junction communication. Cx43(M1) preserved joint integrity and alleviated OA even when treatment began after cartilage damage was established. The antibody preferentially targeted synovial macrophages, suppressing HC activity, ATP and PGE₂ release, and inflammatory gene expression. Macrophage-specific Cx43 deletion reproduced these effects, and Cx43 HC blockade similarly inhibited inflammatory responses in primary human OA synovial macrophages. These findings identify synovial macrophage Cx43 HCs as promising therapeutic targets for OA.