The impact of ACPA on bone loss in patients with rheumatoid arthritis

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Autoantibodies against citrullinated proteins (ACPA) are highly specific for rheumatoid arthritis (RA), precede the clinical onset of disease by years and are the strongest risk factor for bone loss. We have recently shown that ACPA directed against citrullinated vimentin induce bone loss by direct interaction with osteoclast precursors. ACPA also have been shown to form immune complexes with citrullinated proteins in the synovium. Hence, aside from the direct binding of ACPA to citrullinated proteins on the surface of the osteoclasts, the interaction of ACPA containing immune complexes with Fc gamma receptors on osteoclasts may explain ACPA-induced bone loss in RA. Indeed, we found that immune complexes dramatically foster the maturation of osteoclasts and that this interaction is dependent on IgG glycosylation. In the proposed project we thus want to specify the mechanisms of the osteoclast promoting effect of ACPA. In a clinical approach we will examine the impact of the fine specificity ACPA, their glycosylation pattern and allelic variants of the Fc gamma receptors on bone loss in RA patients. These studies will be complemented by in vitro investigations of the involvement of individual Fc-gamma-receptors, signalling and expression of pro-osteoclastic genes and cytokines after challenging preosteoclasts with ACPA.