Dataset Information

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

ABSTRACT:

Background

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. We aimed to define the importance of chemokine signals for migration and activation of OCPs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA).

Methods

PB 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.

Results

The 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.

Conclusions

In 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.

SUBMITTER: Sucur A

PROVIDER: S-EPMC5472975 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RationaleBlacks compared with whites have a greater risk of adverse cardiovascular outcomes. Impaired regenerative capacity, measured as lower levels of circulating progenitor cells (CPCs), is a novel determinant of adverse outcomes; however, little is known about racial differences in CPCs.ObjectiveTo investigate the number of CPCs, PC-mobilizing factors, PC mobilization during acute myocardial infarction and the predictive value of CPC counts in blacks compared with whites.Methods and resultsCPCs were enumerated by flow cytometry as CD45med+ blood mononuclear cells expressing CD34+, CD133+, VEGF2R+, and CXCR4+ epitopes in 1747 subjects, mean age 58.4±13, 55% male, and 26% self-reported black. Patients presenting with acute myocardial infarction (n=91) were analyzed separately. Models were adjusted for relevant clinical variables. SDF-1α (stromal cell-derived factor-1α), VEGF (vascular endothelial growth factor), and MMP-9 (matrix metallopeptidase-9) levels were measured (n=561), and 623 patients were followed for median of 2.2 years for survival analysis. Blacks were younger, more often female, with a higher burden of cardiovascular risk, and lower CPC counts. Blacks had fewer CD34+ cells (-17.6%; [95% confidence interval (CI), -23.5% to -11.3%]; P<0.001), CD34+/CD133+ cells (-15.5%; [95% CI, -22.4% to -8.1%]; P<0.001), CD34+/CXCR4+ cells (-17.3%; [95% CI, -23.9% to -10.2%]; P<0.001), and CD34+/VEGF2R+ cells (-27.9%; [95% CI, -46.9% to -2.0%]; P=0.04) compared with whites. The association between lower CPC counts and black race was not affected by risk factors or cardiovascular disease. Results were validated in a separate cohort of 411 patients. Blacks with acute myocardial infarction had significantly fewer CPCs compared with whites ( P=0.02). Blacks had significantly lower plasma MMP-9 levels ( P<0.001) which attenuated the association between low CD34+ and black race by 19% (95% CI, 13%-33%). However, VEGF and SDF-1α levels were not significantly different between the races. Lower CD34+ counts were similarly predictive of mortality in blacks (hazard ratio, 2.83; [95% CI, 1.12-7.20]; P=0.03) and whites (hazard ratio, 1.79; [95% CI, 1.09-2.94]; P=0.02) without significant interaction.ConclusionsBlack subjects have lower levels of CPCs compared with whites which is partially dependent on lower circulating MMP-9 levels. Impaired regenerative capacity is predictive of adverse outcomes in blacks and may partly account for their increased risk of cardiovascular events.