Identification of a novel chemokine-dependent molecular mechanism underlying Rheumatoid arthritisassociated autoantibody-mediated bone loss

Akilan Krishnamurthy, Vijay Joshua, Aase Haj Hensvold, Tao Jin, Meng Sun, Nancy Vivar, A. Jimmy Ytterberg, Marianne Engström, Cátia Fernandes-Cerqueira, Khaled Amara, Malin Magnusson, Gustaf Wigerblad, Jungo Kato, Juan Miguel Jiménez-Andrade, Kerry Tyson, Stephen Rapecki, Karin Lundberg, Sergiu Bogdan Catrina, Per Johan Jakobsson, Camilla SvenssonVivianne Malmström, Lars Klareskog, Heidi Wähämaa, Anca I. Catrina

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143 Citations (Scopus)

Abstract

Objectives: Rheumatoid arthritis (RA)-specific anticitrullinated 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.

Original languageEnglish
Pages (from-to)721-729
Number of pages9
JournalAnnals of the Rheumatic Diseases
Volume75
Issue number4
DOIs
Publication statusPublished - 2016 Apr 1
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Krishnamurthy, A., Joshua, V., Hensvold, A. H., Jin, T., Sun, M., Vivar, N., Ytterberg, A. J., Engström, M., Fernandes-Cerqueira, C., Amara, K., Magnusson, M., Wigerblad, G., Kato, J., Jiménez-Andrade, J. M., Tyson, K., Rapecki, S., Lundberg, K., Catrina, S. B., Jakobsson, P. J., ... Catrina, A. I. (2016). Identification of a novel chemokine-dependent molecular mechanism underlying Rheumatoid arthritisassociated autoantibody-mediated bone loss. Annals of the Rheumatic Diseases, 75(4), 721-729. https://doi.org/10.1136/annrheumdis-2015-208093