Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin
Ulrike Harre, … , Pierre Jurdic, Georg Schett
Ulrike Harre, … , Pierre Jurdic, Georg Schett
Published April 16, 2012
Citation Information: J Clin Invest. 2012;122(5):1791-1802. https://doi.org/10.1172/JCI60975.
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Research Article Autoimmunity

Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin

Abstract

Autoimmunity is complicated by bone loss. In human rheumatoid arthritis (RA), the most severe inflammatory joint disease, autoantibodies against citrullinated proteins are among the strongest risk factors for bone destruction. We therefore hypothesized that these autoantibodies directly influence bone metabolism. Here, we found a strong and specific association between autoantibodies against citrullinated proteins and serum markers for osteoclast-mediated bone resorption in RA patients. Moreover, human osteoclasts expressed enzymes eliciting protein citrullination, and specific N-terminal citrullination of vimentin was induced during osteoclast differentiation. Affinity-purified human autoantibodies against mutated citrullinated vimentin (MCV) not only bound to osteoclast surfaces, but also led to robust induction of osteoclastogenesis and bone-resorptive activity. Adoptive transfer of purified human MCV autoantibodies into mice induced osteopenia and increased osteoclastogenesis. This effect was based on the inducible release of TNF-α from osteoclast precursors and the subsequent increase of osteoclast precursor cell numbers with enhanced expression of activation and growth factor receptors. Our data thus suggest that autoantibody formation in response to citrullinated vimentin directly induces bone loss, providing a link between the adaptive immune system and bone.

Authors

Ulrike Harre, Dan Georgess, Holger Bang, Aline Bozec, Roland Axmann, Elena Ossipova, Per-Johan Jakobsson, Wolfgang Baum, Falk Nimmerjahn, Eszter Szarka, Gabriella Sarmay, Grit Krumbholz, Elena Neumann, Rene Toes, Hans-Ulrich Scherer, Anca Irinel Catrina, Lars Klareskog, Pierre Jurdic, Georg Schett

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Figure 5

MCV-ACPAs induce bone loss in vivo.

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MCV-ACPAs induce bone loss in vivo. (A) 3-dimensional (top) and 2-dimens...
(A) 3-dimensional (top) and 2-dimensional (bottom) μCT images of the tibial metaphysis of Rag1–/– mice that were left untreated or treated with control IgG or MCV-ACPAs. (B) Structural parameters of the tibial bone (n = 5 per group), including the ratio of bone volume to total volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), and connectivity density (Conn.D). (C) Microphotographs (original magnification, ×400) of tibial bones of Rag1–/– mice treated with either IgG or MCV-ACPAs, stained for osteoclasts (purple stain and arrows) by histochemical detection of TRAP. Histomorphometric quantification of osteoclast number and osteoblast number (N.Ob) on the tibial bone surface (BS) is also shown. *P < 0.05.