Pathogenetic insights from the treatment of rheumatoid arthritis

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

Ulrike Harre, Dan Georgess, Holger Bang … (2012)

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.

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Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss

Akilan Krishnamurthy, Vijay Joshua, Aase Hensvold … (2015)

Objectives Rheumatoid arthritis (RA)-specific anti-citrullinated protein/peptide antibodies (ACPAs) appear before disease onset and are associated with bone destruction. We aimed to dissect the role of ACPAs in osteoclast (OC) activation and to identify key cellular mediators in this process. Methods Polyclonal ACPA were isolated from the synovial fluid (SF) and peripheral blood of patients with RA. Monoclonal ACPAs were isolated from single SF B-cells of patients with RA. OCs were developed from blood cell precursors with or without ACPAs. We analysed expression of citrullinated targets and peptidylarginine deiminases (PAD) enzymes by immunohistochemistry and cell supernatants by cytometric bead array. The effect of an anti-interleukin (IL)-8 neutralising antibody and a pan-PAD inhibitor was tested in the OC cultures. Monoclonal ACPAs were injected into mice and bone structure was analysed by micro-CT before and after CXCR1/2 blocking with reparixin. Results Protein citrullination by PADs is essential for OC differentiation. Polyclonal ACPAs enhance OC differentiation through a PAD-dependent IL-8-mediated autocrine loop that is completely abolished by IL-8 neutralisation. Some, but not all, human monoclonal ACPAs derived from single SF B-cells of patients with RA and exhibiting distinct epitope specificities promote OC differentiation in cell cultures. Transfer of the monoclonal ACPAs into mice induced bone loss that was completely reversed by the IL-8 antagonist reparixin. Conclusions We provide novel insights into the key role of citrullination and PAD enzymes during OC differentiation and ACPA-induced OC activation. Our findings suggest that IL8-dependent OC activation may constitute an early event in the initiation of the joint specific inflammation in ACPA-positive RA.

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Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies.

Arnd Kleyer, Stephanie Finzel, Jürgen Rech … (2014)

Anticitrullinated protein antibodies (ACPA) are a major risk factor for bone loss in rheumatoid arthritis (RA). We have recently shown that ACPA directly induce bone loss by stimulating osteoclast differentiation. As ACPA precede the clinical onset of RA by years, we hypothesised that ACPA positive healthy individuals may already show skeletal changes.

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Title: The Lancet

Abbreviated Title: The Lancet

Publisher: Elsevier BV

ISSN (Print): 01406736

Publication date Created: June 2017

Publication date (Print): June 2017

Volume: 389

Issue: 10086

Pages: 2328-2337

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DOI: 10.1016/S0140-6736(17)31472-1

PubMed ID: 28612747

SO-VID: fb91e6f8-b19f-4c2a-9f66-648c0d9ce520

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Pathogenetic insights from the treatment of rheumatoid arthritis

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Most cited references 68

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

Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss

Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies.

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