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Chemokine signals are crucial for enhanced homing and differentiation of circulating osteoclast progenitor cells

  • Sucur, Alan1, 2
  • Jajic, Zrinka3
  • Artukovic, Marinko4
  • Matijasevic, Marina Ikic4
  • Anic, Branimir5
  • Flegar, Darja1, 2
  • Markotic, Antonio1, 2
  • Kelava, Tomislav1, 2
  • Ivcevic, Sanja1, 2
  • Kovacic, Natasa1, 6
  • Katavic, Vedran1, 6
  • Grcevic, Danka1, 2
  • 1 University of Zagreb School of Medicine, Croatian Institute for Brain Research, Salata 12, Zagreb, HR 10000, Croatia , Zagreb (Croatia)
  • 2 University of Zagreb School of Medicine, Department of Physiology and Immunology, Salata 3b, Zagreb, HR 10000, Croatia , Zagreb (Croatia)
  • 3 University of Zagreb School of Medicine, Department of Rheumatology, Physical Medicine and Rehabilitation, Clinical Hospital Center “Sestre Milosrdnice”, Vinogradska cesta 29, Zagreb, HR 10000, Croatia , Zagreb (Croatia)
  • 4 Clinical Hospital “Sveti Duh”, Department of Clinical Immunology and Pulmonology, Sveti Duh 64, Zagreb, HR 10000, Croatia , Zagreb (Croatia)
  • 5 Clinical Hospital Center “Zagreb”, Department of Clinical Immunology and Rheumatology, Kispaticeva 12, Zagreb, HR 10000, Croatia , Zagreb (Croatia)
  • 6 University of Zagreb School of Medicine, Department of Anatomy, Salata 11, Zagreb, HR 10000, Croatia , Zagreb (Croatia)
Published Article
Arthritis Research & Therapy
Springer Science and Business Media LLC
Publication Date
Jun 15, 2017
DOI: 10.1186/s13075-017-1337-6
Springer Nature


BackgroundThe peripheral blood (PB) monocyte pool contains osteoclast progenitors (OCPs), which contribute to osteoresorption in inflammatory arthritides and are influenced by the cytokine and chemokine milieu. We aimed to define the importance of chemokine signals for migration and activation of OCPs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA).MethodsPB and, when applicable, synovial fluid (SF) samples were collected from 129 patients with RA, 53 patients with PsA, and 110 control patients in parallel to clinical parameters of disease activity, autoantibody levels, and applied therapy. Receptors for osteoclastogenic factors (CD115 and receptor activator of nuclear factor-κB [RANK]) and selected chemokines (CC chemokine receptor 1 [CCR1], CCR2, CCR4, CXC chemokine receptor 3 [CXCR3], CXCR4) were determined in an OCP-rich subpopulation (CD3−CD19−CD56−CD11b+CD14+) by flow cytometry. In parallel, levels of CC chemokine ligand 2 (CCL2), CCL3, CCL4, CCL5, CXC chemokine ligand 9 (CXCL9), CXCL10, and CXCL12 were measured using cytometric bead array or enzyme-linked immunosorbent assay. Sorted OCPs were stimulated in culture by macrophage colony-stimulating factor and receptor activator of nuclear factor-κB ligand, and they were differentiated into mature osteoclasts that resorb bone. Selected chemokines (CCL2, CCL5, CXCL10, and CXCL12) were tested for their osteoclastogenic and chemotactic effects on circulatory OCPs in vitro.ResultsThe OCP population was moderately enlarged among PB cells in RA and correlated with levels of tumor necrosis factor-α (TNF-α), rheumatoid factor, CCL2, and CCL5. Compared with PB, the RANK+ subpopulation was expanded in SF and correlated with the number of tender joints. Patients with PsA could be distinguished by increased RANK expression rather than total OCP population. OCPs from patients with arthritis had higher expression of CCR1, CCR2, CCR4, CXCR3, and CXCR4. In parallel, patients with RA had increased levels of CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10, with significant elevation in SF vs PB for CXCL10. The subset expressing CXCR4 positively correlated with TNF-α, bone resorption marker, and rheumatoid factor, and it was reduced in patients treated with disease-modifying antirheumatic drugs. The CCR4+ subset showed a significant negative trend during anti-TNF treatment. CCL2, CCL5, and CXCL10 had similar osteoclastogenic effects, with CCL5 showing the greatest chemotactic action on OCPs.ConclusionsIn our study, we identified distinct effects of selected chemokines on stimulation of OCP mobilization, tissue homing, and maturation. Novel insights into migratory behaviors and functional properties of circulatory OCPs in response to chemotactic signals could open ways to new therapeutic targets in RA.

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