Abstract
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.
Highlights
The 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
Patients with rheumatoid arthritis have highly active disease with elevated inflammatory, osteoresorptive, and autoimmune indicators The demographic and clinical characteristics showed that the majority of patients with RA included in the study had a chronic course of active disease (Table 1) with multiple joints affected and enhanced osteoresorption
We evaluated chemokine osteoclastogenic and chemotactic effects on nonadherent cells harvested after overnight culturing of peripheral blood mononuclear cells (PBMCs) with 35 ng/ml macrophage colony-stimulating factor (M-CSF)
Summary
The 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. Rheumatoid arthritis (RA) is a systemic inflammatory disease manifesting predominantly as chronic affection of multiple joints and osteodestruction, and involving complex interactions between the immune system, extracellular matrix, and bone cells [1]. Osteoclasts (OCs) are multinucleated cells with the unique ability to resorb bone. They develop by fusion of hematopoietic precursors belonging to the monocyte/ macrophage lineage. OCs express receptors for two crucial regulators of their differentiation and maturation: macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor- κB ligand (RANKL, CD254). The receptor for colony-stimulating factor-1 (cFms, CD115, M-CSF receptor) appears at early developmental stages of the myeloid lineage, whereas receptor activator of nuclear factor-κB (RANK; CD265) is expressed on committed osteoclast progenitors (OCPs) and is crucial for OC survival and activation [5,6,7]. Elevated levels of a wide range of proinflammatory cytokines (interleukin-1 [IL-1], IL-6, IL-15, IL-17, IL-18, IL-21, IL-22, IL-23, tumor necrosis factor-α [TNF-α]) and chemokines (CC chemokine ligand 2 [CCL2], CCL3, CCL4, CCL5) act in synergy with M-CSF/RANK signals to promote osteoclastogenesis [8, 9]
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