Local complement dysregulation in osteoarthritis: from C3/C5 activation to membrane attack complex–driven joint damage

Joint inflammation can persist after the initial injury in osteoarthritis (OA). Local complement activation offers one explanation. Damaged matrix and cellular debris can activate complement, while chondrocytes and synovial cells supply some of its components. C3 and C5 cleavage then generate inflammatory mediators and initiate membrane attack complex formation. Human studies document these events in diseased joints, but most causal evidence comes from animal models and cartilage cultures. This mini review examines what that evidence supports and where the proposed feedback loop remains uncertain. We update earlier reviews with recent findings on terminal-complement-associated senescence and metabolic stress, while distinguishing OA evidence from mechanisms proposed in other diseases. We argue that terminal deposition should be interpreted alongside regulatory protection and cell viability, rather than as an isolated marker of disease activity. Likewise, complement abundance in synovial fluid cannot establish local synthesis or predict treatment response. Local terminal inhibition and restoration of regulatory protection merit further study. Experimental C5a receptor 1 (C5aR1) blockade partly reduces pain-like behavior in a chemical OA model, but sensory mechanisms and clinical benefit remain unresolved. The next step is to identify joints with persistent, damaging activation and determine whether timed intervention can interrupt it without compromising repair or host defense.