Fra1 Controls Rheumatoid Factor Autoantibody Production by Bone Marrow Plasma Cells and the Development of Autoimmune Bone Loss

Next to proinflammatory cytokines, autoimmunity has been identified as a key trigger for osteoclast activation and bone loss. IgG‐rheumatoid factor (IgG‐RF) immune complexes, which are present in patients with rheumatoid arthritis, were shown to boost osteoclast differentiation. To date, the regulation of IgG‐RF production in the absence of inflammatory triggers is unknown. Herein, we describe Fra1 as a key checkpoint that controls IgG‐RF production by plasma cells and regulates autoimmune‐mediated bone loss. Fra1 deficiency in B cells ( Fra1 ΔBcell ) led to increased IgG1‐producing bone marrow plasma cells, enhanced IgG‐RF production, and increased bone loss associated with elevated osteoclast numbers after immunization. The effect of IgG‐RF on osteoclasts in vitro and on osteoclasts associated with bone loss in vivo was dependent on FcγR, especially FcγR3. Furthermore, immunization of WT mice with T‐cell‐dependent antigens induced a significant and robust decrease in Fra1 expression in bone marrow B cells, which was followed by increased IgG1 production and the induction of osteoclast‐mediated bone loss. Overall, these data identify Fra1 as a key mediator of IgG‐RF production and autoimmune‐mediated bone loss. © 2019 American Society for Bone and Mineral Research.