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

Abstract

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 (Fra1ΔBcell) 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.

The Fra-1: Novel role in regulating extensive immune cell states and affecting inflammatory diseases

“…However, subsequent studies have pointed out that Fra-1 can inhibit the production and development of plasma cells by regulating the direct combination with the Prdm1/Bimp1(PR/SET Domain 1/B lymphocyte induced maturation protein 1) promoter ( 142 ). In addition, the activation of B cells by TD antigen can reduce the expression of Fra-1, which can control the production of IgG-RF and inhibit the activation of osteoclasts driven by immune complexes ( 143 ). Therefore Fra-1 may be used as a regulator to block the negative effects of autoimmunity by inhibiting the formation of immune complexes.…”

“…Different from the absence of other AP-1 members, c-Fos deficient mice have more severe arthritis ( 177 ). Overexpression of Fra-1 in CD4 + T cells can bind to JunB as a downstream target of Stat3 to induce Th17 cell differentiation and promote autoimmune arthritis ( 143 ). Inhibition of AP-1 activity can prevent acute graft-versus-host disease (aGVHD) by altering the differentiation of CD4 + T cells, such as reduced Th17/Th1 population and increased Treg population ( 163 ).…”

Current view on the pathogenic role of anti-citrullinated protein antibodies in rheumatoid arthritis

“…Importantly, osteoclasts express several Fcγ receptors and IgG containing ICs can activate osteoclasts and increase bone loss independently of the antigen specificity. [31][32][33] The osteoclast activating effect of IgGs appears to be dependent on the Fc glycosylation status, IgG isotype and the different distribution of Fcγ receptors in physiological compared with inflammatory conditions. 34 If the ACPA containing ICs exert similar Fc-dependent effects, it still remains to be demonstrated.…”

Effects of Autoantibodies on Osteoclasts

“…Most effects of antibodies on osteoclasts seem to be mediated by binding of complexed IgG (e. g. immune complexes) to low affinity FcγRs. Mice with increased autoantibody formation caused by the loss of B cell checkpoints display systemic osteoporosis due to osteoclast activation by immune complexes [11,12]. Stimulation of osteoclasts with serum from these mice resulted in increased osteoclast formation and resorption activity.…”