Identification of a Novel Chemokine-Dependent Molecular Mechanism Underlying Rheumatoid Arthritis-Associated Autoantibody-Mediated Bone Destruction

Akilan Krishnamurthy¹, Vijay Joshua², Aase Haj Hensvold³, Tao Jin⁴, Meng Sun³, Marianne Engström³, Khaled Amara¹, Malin MAgnusson⁴, Camilla Svensson⁵, Vivianne Malmström³, L. Klareskog¹, Heidi Wähämaa³ and Anca I Catrina³, ¹Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden, ²Unit of Rheumatology, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden, ³Rheumatology Unit, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden, ⁴Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden, Gothenberg, Sweden, ⁵Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: anti-CCP antibodies, bone biology and rheumatoid arthritis (RA)

Session Information

Date: Tuesday, November 10, 2015

Title: Biology and Pathology of Bone and Joint: Bone Remodeling and Metabolism

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose:

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 (PB) of RA patients. Monoclonal ACPAs were isolated from single SF B-cells of RA patients. OCs were developed from blood cell precursors with or without ACPAs. We analyzed expression of citrullinated targets and PAD enzymes by immunohistochemistry and cell supernatants by cytometric bead array. Monoclonal ACPAs were injected into mice and bone structure was analyzed by micro-computer tomography. The effect of an anti-IL-8/CXCL8 neutralizing antibody was tested in the OC cultures and in ACPA treated mice.

Results:

Polyclonal ACPAs enhanced osteoclastogenesis from CD14-dervied macrophages of either healthy donors (fold increase of 1.6±0.4 for osteoclasts number and 2.0±0.6 for bone resorption area as compared to control IgGs) or ACPA-positive RA patients (fold increase of 1.8±0.6 for OC number and 2.3±0.7 for bone resorption as compared to control IgGs). PB derived ACPAs were equally effective with SF ACPAs. Two of the tested monoclonal ACPAs (reacting with the immunodominant cit-epitopes of enolase and vimentin, had similar effects), whereas 2 others monoclonal ACPAs (mainly reacting with cit-fibrinogen peptides) failed to induce osteoclastogenesis. Fab fragments of the active monoclonal ACPAs retained similar effects. Increased osteoclastogenesis was associated with significantly higher levels of IL-8 levels in cultures supernatants of ACPA as compared to control IgGs-treated OCs (fold increase of 2.0±0.5) and completely abolished by neutralizing anti IL-8 antibodies. Transfer of the monoclonal ACPAs into mice induced trabecular bone loss that was completely reversed by the IL-8 antagonist reparixin.

Conclusion:

We provide novel insights into the key role of IL-8 during ACPA-induced OC activation. Our results open the way for preclinical studies to test the therapeutic and preventive effect of IL-8 blocking agents in models of RA and eventually also in ACPA-positive individuals at risk of developing RA.

Disclosure: A. Krishnamurthy, None; V. Joshua, None; A. H. Hensvold, None; T. Jin, None; M. Sun, None; M. Engström, None; K. Amara, None; M. MAgnusson, None; C. Svensson, None; V. Malmström, None; L. Klareskog, None; H. Wähämaa, None; A. I. Catrina, None.

To cite this abstract in AMA style:

Krishnamurthy A, Joshua V, Hensvold AH, Jin T, Sun M, Engström M, Amara K, MAgnusson M, Svensson C, Malmström V, Klareskog L, Wähämaa H, Catrina AI. Identification of a Novel Chemokine-Dependent Molecular Mechanism Underlying Rheumatoid Arthritis-Associated Autoantibody-Mediated Bone Destruction [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/identification-of-a-novel-chemokine-dependent-molecular-mechanism-underlying-rheumatoid-arthritis-associated-autoantibody-mediated-bone-destruction/. Accessed .

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