Figure 1. Complement's vicious cycle in osteoarthritis. Joint damage can activate a self-perpetuating cycle of complement activation and cartilage damage that leads to osteoarthritis.

Joint damage from injury or surgery releases extracellular matrix (ECM) components [a], such as fibromodulin and aggrecan, into the synovial fluid that activate the complement system and upregulate complement 5 (C5) [b]. Upon cleavage from C5, C5b recruits other complement factors (C6-C9) to form the complement C5b-9 membrane attack complex (MAC) [c] that targets chondrocytes and either kills them to cause cartilage damage [d] or induces expression of proinflammatory monocyte chemoattractant protein-1 (MCP-1; CCL2), expression of additional C5 and secretion of ECM-degrading enzymes such as matrix metalloproteinase 13 (MMP13) and ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5) [e], thereby continuing the cartilage-damaging cycle [a-e].

Ergidina, a recombinant human minibody against C5 fused with an arginine-glycine-aspartic acid motif, from Adienne Pharma & Biotech, is in preclinical testing to treat ischemia/reperfusion injury.