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Autoantibodies against proteins marked with a type of post-translational modification called citrullination are found in people with rheumatoid arthritis and are one of the strongest risk factors for bone destruction in this disease. A recent study now directly links the formation of these antibodies to bone loss in rheumatoid arthritis, indicating that the autoantibodies act on osteoclasts, the bone cells responsible for bone resorption (J. Clin. Invest. 122, 1791–1802).

Ulrike Harre et al. found that the presence of anti–citrullinated protein antibodies (ACPAs) is associated with increased amounts of serum markers of bone resorption in people with rheumatoid arthritis. They affinity-purified autoantibodies against mutated citrullinated vimentin from patients; the production of these antibodies is highly specific to people with rheumatoid arthritis. In vitro, these purified ACPAs bound to the surface of osteoclast progenitors and induced their differentiation into mature osteoclasts and also increased osteoclast-mediated bone resorption.

The authors then injected the purified ACPAs into immunodeficient Rag1−/− mice, leading to systemic bone loss. This bone loss seemed to be mediated through an increase in osteoclast precursor numbers and increased osteoclast differentiation in response to ACPAs. These effects may depend on tumor necrosis factor-a, as the authors observed increased amounts of this inflammatory cytokine, which is known to induce osteoclastogenesis, in the mice treated with ACPAs.

This work thus provides new insights into the interactions between the immune system, inflammation and bone in rheumatoid arthritis.