Background Autoantibodies against citrullinated proteins (ACPA) are amongst the strongest risk factors for bone destruction in rheumatoid arthritis (RA)
Objectives We therefore hypothesized that these autoantibodies directly influence bone metabolism.
Methods A strong and specific association between autoantibodies against citrullinated proteins and serum markers for osteoclast-mediated bone resorption was found in the serum of RA patients. Moreover, human osteoclasts expressed enzymes eliciting protein citrullination such as PAD2 and revealed specific inducible N-terminal citrullination of vimentin during their differentiation process. Affinity purified human autoantibodies against mutated citrullinated vimentin (MCV) not only bound to the osteoclast surface, but also lead to a robust induction of osteoclastogenesis and bone resorptive activity. Adoptive transfer of human MCV antibodies into RAG1-/- mice was followed by induction of osteopenia and increased osteoclastogenesis in vivo. This effect was based on the inducible release of TNFa from osteoclast precursors and the subsequent increase of CD11b+ osteoclast precursor cell numbers with enhanced expression of RANK and CSF1 receptors in vivo.
Conclusions Our data thus suggest that autoantibody formation to citrullinated vimentin directly induces bone loss and provides a novel link between the adaptive immune system and bone.
Disclosure of Interest None Declared