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

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1337-6) contains supplementary material, which is available to authorized users.

Inhibition of radiographic progression across levels of composite index-defined disease activity in patients with active psoriatic arthritis treated with intravenous golimumab: results from a phase-3, double-blind, placebo-controlled trial

“…Results are shown at week 24 (a) and week 52 (b). CDAI, Clinical Disease Activity Index; HDA, high disease activity; IV, intravenous; LDA, low disease activity; ModDA, moderate disease activity; PsA, psoriatic arthritis; SD, standard deviation; SHS, -Sharp/van der Heijde score OCP populations correlated with peripheral blood TNFα levels [37]. Thus, observations to date suggest TNFα is pivotal in promoting OCP formation.…”

Evaluation of chemokine CXCL10 in human gingival crevicular fluid, saliva, and serum as periodontitis biomarker

“… 29 With regard to CXCL10’s role in osteoclast recruitment, a recent report shows that chemokine signals are crucial for enhanced homing and differentiation of circulating osteoclast progenitor cells. 10 The study identified distinct effects of selected chemokines on the stimulation of osteoclast progenitor cell mobilization, tissue homing, and maturation.…”

“…Chemokine CXCL10, also known as IP-10, appears to have a direct influence on osteoclastogenesis for its involvement in leukocyte and osteoclast precursor diapedesis 10 and subsequent presence in the periodontal environment. CXCL10 is a 10 kDa protein and functionally categorized as an “inflammatory” chemokine.…”

<p>Role of Chemokines and Chemokine Receptors in Rheumatoid Arthritis</p>

“…48 RA patients exhibit increased levels of CCL2, CCL3, CCL4, and CXCL10 in plasma as well as synovial fluid. [49][50][51][52][53] On the other hand, CCL5 showed an increased level in the plasma but a reduction in synovial fluid of RA patients. 49 CCL2 is a potent chemoattractant for macrophages, while CCL3 recruits various lymphocytes, monocytes, and eosinophils.…”

“…[49][50][51][52][53] On the other hand, CCL5 showed an increased level in the plasma but a reduction in synovial fluid of RA patients. 49 CCL2 is a potent chemoattractant for macrophages, while CCL3 recruits various lymphocytes, monocytes, and eosinophils. 54 Elevated CCL2 level in RA has been strongly associated with an increase in joint infiltration by immune cells, specifically macrophages.…”