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Basic and translational research
Extended report
Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss
  1. Akilan Krishnamurthy1,
  2. Vijay Joshua1,
  3. Aase Haj Hensvold1,
  4. Tao Jin2,
  5. Meng Sun1,
  6. Nancy Vivar1,
  7. A Jimmy Ytterberg1,3,
  8. Marianne Engström1,
  9. Cátia Fernandes-Cerqueira1,
  10. Khaled Amara1,
  11. Malin Magnusson2,
  12. Gustaf Wigerblad4,
  13. Jungo Kato4,
  14. Juan Miguel Jiménez-Andrade5,
  15. Kerry Tyson6,
  16. Stephen Rapecki6,
  17. Karin Lundberg1,
  18. Sergiu-Bogdan Catrina7,
  19. Per-Johan Jakobsson1,
  20. Camilla Svensson4,
  21. Vivianne Malmström1,
  22. Lars Klareskog1,
  23. Heidi Wähämaa1,
  24. Anca I Catrina1
  1. 1Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
  2. 2Department of Rheumatology and Inflammation Research, Institution of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  3. 3Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
  4. 4Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
  5. 5UCB Unidad Académica Multidisciplinaria Reynosa Aztlán, Universidad Autónoma de Tamaulipas, Reynosa, Tamaulipas, México
  6. 6UCB Pharma, Slough, UK
  7. 7Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  1. Correspondence to Dr Anca I Catrina, Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm S-17176, Sweden; anca.catrina{at}ki.se

Abstract

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 While ACPA may induce OC activation, the conclusions concerning the specificity of these observations require additional experiments before detailed mechanisms can be elucidated. Further, it is also not yet clear if ACPA are pathogenetically involved in the initiation of the joint specific inflammation in ACPA-positive RA or not.

  • Ant-CCP
  • Autoantibodies
  • Early Rheumatoid Arthritis

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/annrheumdis-2015-208093

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