Osteoarthritis (OA) pain is a leading cause of disability globally, yet effective treatments remain limited. Synovial macrophages play a crucial role in OA, releasing nociceptive factors that contribute to pain. This study hypothesized that inhibiting macrophage activation, rather than depleting them, could reduce pain without exacerbating tissue damage. Researchers used a rat model of knee OA to investigate the role of STAT signaling in synovial macrophages and its impact on pain outcomes. RNA sequencing identified key macrophage activation pathways, with a focus on STAT1 and STAT6 signaling.
The study found that STAT signaling is a significant mediator of synovial macrophage activation in OA. While macrophage depletion reduced pain, it also increased fibrosis and vascularization in the synovial tissue. In contrast, inhibiting STAT6 in macrophages led to significant and sustained reductions in mechanical pain sensitivity and inflammation without worsening synovial or cartilage damage. Additionally, STAT6 inhibition had minimal adverse effects on healthy chondrocyte gene expression, suggesting it could be a promising strategy for managing OA pain without accelerating tissue damage.
Reference: Blackler G, Lai-Zhao Y, Klapak J, et al. Targeting STAT6-mediated synovial macrophage activation improves pain in experimental knee osteoarthritis. Arthritis Res Ther. 2024 Mar 20;26(1):73. doi: 10.1186/s13075-024-03309-6. PMID: 38509602; PMCID: PMC10953260.
