title: 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.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Harre
authors.forename: Dan
authors.initials: D
authors.lastname: Georgess
authors.forename: Holger
authors.initials: H
authors.lastname: Bang
authors.forename: Aline
authors.initials: A
authors.lastname: Bozec
authors.forename: Roland
authors.initials: R
authors.lastname: Axmann
authors.forename: Elena
authors.initials: E
authors.lastname: Ossipova
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Jakobsson
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baum
authors.forename: Falk
authors.initials: F
authors.lastname: Nimmerjahn
authors.forename: Eszter
authors.initials: E
authors.lastname: Szarka
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sarmay
authors.forename: Grit
authors.initials: G
authors.lastname: Krumbholz
authors.forename: Elena
authors.initials: E
authors.lastname: Neumann
authors.forename: Rene
authors.initials: R
authors.lastname: Toes
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Scherer
authors.forename: Anca Irinel
authors.initials: AI
authors.lastname: Catrina
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.forename: Pierre
authors.initials: P
authors.lastname: Jurdic
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000302:isolation & purification / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood; D001862:Bone Resorption / Q000276:immunology*; D001842:Bone and Bones / Q000276:immunology / Q000473:pathology; D016022:Case-Control Studies; D002454:Cell Differentiation; D002478:Cells, Cultured; D002956:Citrulline / Q000276:immunology*; D024042:Collagen Type I / Q000097:blood; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014746:Vimentin / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D024042:Collagen Type I; D014409:Tumor Necrosis Factor-alpha; D014746:Vimentin; D002956:Citrulline; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; C552151:peptidylarginine deiminase 4, mouse