Alpha-2-Macroglobulin-Enriched Plasma Modulates Inflammatory and Proteolytic Pathways in Experimental Equine Musculoskeletal Models

Joint inflammation and extracellular matrix degradation are major contributors to the development of equine osteoarthritis and reduced athletic performance. Alpha-2-macroglobulin is a naturally occurring broad-spectrum inhibitor of proteases and inflammatory mediators that has emerged as a promising orthobiologic therapy. This study investigated the anti-inflammatory and matrix-protective effects of alpha-2-macroglobulin-enriched plasma in complementary in vitro and ex vivo equine models. Primary equine chondrocytes and synoviocytes isolated from healthy horses were stimulated with interleukin-1β or lipopolysaccharide and treated with alpha-2-macroglobulin-enriched plasma or matched platelet-poor plasma. In parallel, an equine tendon explant model challenged with collagenase was used to evaluate extracellular matrix preservation. Alpha-2-macroglobulin-enriched plasma significantly reduced the production of tumor necrosis factor-α, interleukin-6, and matrix metalloproteinase-13, downregulated interleukin-1β gene expression, and partially restored collagen type II expression in inflamed joint cells compared with platelet-poor plasma. In tendon explants, treatment preserved tissue architecture, reduced collagen degradation, and improved histological indices of matrix integrity under proteolytic challenge. These findings demonstrate that alpha-2-macroglobulin-enriched plasma exerts anti-inflammatory, anti-catabolic, and matrix-protective effects in experimental equine tissues. The results provide mechanistic support for the development of alpha-2-macroglobulin-based orthobiologic therapies as a complementary strategy for the management of synovitis and early osteoarthritis in horses.