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such binding promotes osteoclast differentiation and osteolytic function in vitro Osteoclast differentiation is dependent on the citrullination of proteins by protein-arginine deiminases Both Fc-dependent and Fc-independent mechanisms are involved in ACPA-mediated osteoclast activation Binding of ACPAs to osteoclasts induces the production of the chemokine IL-8 Infusion of ACPAs into mice causes IL-8-dependent bone loss and IL-8-mediated pain behaviour The unique role of citrullination in osteoclast differentiation and ACPA-induced osteoclast activation might explain important features of the gradual development of rheumatoid arthritis, including why the joints are targeted Abstract A key unanswered question in the pathophysiology of rheumatoid arthritis (RA) is how systemic autoimmunity progresses to joint-specific inflammation