Targeting Macrophage Connexin 43 Hemichannels Suppresses Synovial Inflammation and Osteoarthritis
Osteoarthritis (OA) is the most common chronic joint disease and a leading cause of disability worldwide, yet no disease-modifying therapies are available. Although OA has traditionally been viewed as a cartilage-centered degenerative disease, growing evidence suggests that synovial inflammation is a critical driver of disease progression. However, the upstream mechanisms and actionable targets…
Osteoarthritis, a widespread joint ailment leading to disability globally, currently lacks disease-modifying treatments. Although historically considered a cartilage-centric degenerative condition, recent research highlights synovial inflammation as a key catalyst for disease advancement. However, the driving forces and targets to tackle this inflammatory response remain elusive.
Connexin 43 (Cx43), a crucial regulator of musculoskeletal balance that forms gap junctions and hemichannels (HCs), is overexpressed in osteoarthritic cartilage and synovium, yet the precise involvement of Cx43 channels is unclear.
In this study, selective inhibition of Cx43 HCs was found to halt OA progression in a murine post-traumatic OA model. By employing adeno-associated virus (AAV)-mediated gene deletion, it was observed that Cx43 knockdown in joint tissues decreased cartilage loss, synovial growth, subchondral bone hardening, and OA-related pain. To focus on HC-specific functions, a monoclonal antibody, Cx43(M1), was developed to block Cx43 HCs without altering junctional communication.
Cx43(M1) maintained cartilage health, curbed synovial inflammation, and alleviated pain, even when introduced post-damage. This antibody predominantly accumulated in synovial macrophages, where it suppressed HC activity, lowered ATP and PGE2 release, and dampened pro-inflammatory gene expression. Macrophage-specific Cx43 deletion produced comparable protective outcomes, and Cx43 HC blockade in primary human OA synovial macrophages also inhibited inflammatory and catabolic reactions.
These findings identify synovial macrophage Cx43 HCs as upstream contributors to OA and advocate for a shift from a primarily cartilage-focused approach to a synovial macrophage-targeted intervention strategy.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
