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

Campus virtuales : revista científica iberoamericana de tecnología educativa

Resumen basado en el de la publicaciónResumen en inglésSe describe la creación y contenidos de una plataforma de e-learning llamada AprendeBn para el sistema educativo panameño. Se comienza realizando un análisis de la problemática educativa en Panamá a partir de los informes del Ministerio de Educación (MEDUCA). Posteriormente se hace una evaluación comparativa de las principales plataformas de este tipo y se describen las características más relevantes de cada una de ella. Se pretende desarrollar una plataforma para Panamá que se enfoca en el estudiante y educador panameño de los niveles de premedia y media. En la plataforma se utiliza el formato, las mejores ideas y la experiencia de otras de similares características pero teniendo en cuenta los factores locales y los objetivos del sistema educativo panameño. Se persigue contar con un recurso tecnológico y social educativo, donde tanto estudiantes como educadores cuenten con contenidos actualizados de los programas oficialesES

Additional file 1: Figure S1. of Chemokine signals are crucial for enhanced homing and differentiation of circulating osteoclast progenitor cells

Increased frequency of osteoclast progenitor cells and subsets expressing chemokine receptors in peripheral blood and synovial fluid samples of patients with RA and PsA. a Proportion of OCPs, subsets expressing macrophage colony-stimulating factor receptor (CD115) and RANK in peripheral blood of CTRL subjects and patients with arthritis, and SF samples (SF RA, SF PsA), assessed by flow cytometry. b Concentrations of soluble RANKL in SF of arthritic patients, measured by ELISA. c Chemokine receptor expression on OCPs in peripheral blood of CTRL subjects and patients with arthritis, and SF of patients with arthritis, assessed by flow cytometry. Values are presented as medians (middle line), with boxes representing IQR, whiskers representing 1.5 times the IQR, and squares or circles representing outliers. Group-to-group comparisons were performed using a nonparametric Mann-Whitney U test, and p values <0.05 are shown for comparisons made between PsA and other groups. Previously shown p values for comparisons between RA and CTRL groups (Figs. 2 and 3) are not shown again for the sake of visual clarity. (TIF 1768 kb

Chemotactic and immunoregulatory properties of bone cells are modulated by endotoxin-stimulated lymphocytes

In our study, we explored the bidirectional communication via soluble factors between bone cells and endotoxin-stimulated splenic lymphocytes in an in vitro coculture model that mimics the inflammatory environment. Both the ability of lymphocytes to affect differentiation and immune properties of bone cells, osteoblasts (OBL) and osteoclasts (OCL), and of bone cells to modulate cytokine and activation profile of endotoxin-stimulated lymphocytes were tested. LPS-pulsed lymphocytes enhanced OCL but inhibited OBL differentiation and increased the RANKL/OPG ratio, and, at the same time, upregulated chemotactic properties of bone cells, specifically CCL2, CCL5, and CXCL10 in OCL and CCL5 and CXCL13 in OBL. In parallel, bone cells had immunosuppressive effects by downregulating the lymphocyte expression of interleukin (IL)-1, IL-6, TNF-α and co-stimulatory molecules. OCL stimulated the production of osteoclastogenic cytokine RANKL in T lymphocytes. The anti-inflammatory effect, especially of OBL, suggests a possible compensatory mechanism to limit the inflammatory reaction during infection