Peripheral Blood Mononuclear Phagocytes From Patients With Chronic Periodontitis Are Primed for Osteoclast Formation

• Localización: Journal of periodontology, ISSN 0022-3492, Nº. 4, 2014, págs. 72-81
• Idioma: inglés
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• Resumen

  • Background: During inflammatory periodontal disease, peripheral blood mononuclear cells (PBMCs) are attracted to bone and differentiate into active bone-resorbing osteoclasts (OCs), thus providing evidence that the impact of chronic periodontitis (CP) on the activity of circulating mononuclear cells is of central importance. The authors test the hypothesis that peripheral blood mononuclear phagocytes (PBMPs) from patients with CP are activated and more susceptible to differentiation into OCs, which in turn would lead to more intense bone resorption.

    Methods: In vitro cytokine production by both unstimulated and lipopolysaccharide-stimulated PBMCs from individuals with (n = 10) or without (n = 12) periodontitis was determined by cytokine array. OC differentiation from CD14+ PBMCs was induced by receptor activator of nuclear factor-kappa B ligand (RANKL), either alone or in the presence of macrophage colony-stimulating factor (M-CSF). PBMC differentiation to OCs was confirmed by tartrate-resistant acid phosphatase staining; bone resorbing activity was assessed by using an osteologic plate assay (bone resorption pit formation).

    Results: PBMCs from patients with CP produced tumor necrosis factor-a and higher amounts of interferon-?, interleukin (IL)-1a, IL-1ß, IL-1ra, CXC motif chemokine 10, macrophage migration inhibitory factor, macrophage inflammatory protein (MIP)-1a, and MIP-1ß than the control cells. OC differentiation was induced by RANKL alone in PBMCs from patients with CP, but not in PBMCs from the healthy controls, which required the addition of M-CSF. In addition, PBMC-derived OCs from patients with CP showed significantly higher resorption activity than that observed in the healthy controls. Also, the circulating concentrations of M-CSF were significantly higher in patients with CP than in the control participants.

    Conclusions: These data indicate that in patients with CP, circulating PBMCs are primed for increased proinflammatory activity and that M-CSF plays a central role in this process by increasing OC formation and the consequent bone resorption activity.

    The relationship between periodontal and systemic diseases has been the focus of numerous studies, including preterm low birth weight, cardiovascular disease including myocardial infarction, stroke, diabetes mellitus, and rheumatoid arthritis (RA).1-4 One of the biologic mechanisms proposed for this linkage is an increase in the plasma levels of several inflammatory mediators, such as interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-a, prostaglandin E2 (PGE2), C-reactive protein (CRP), and free radicals,1-4 in patients with chronic periodontitis (CP). For example, Higashi et al.5 showed that CP is associated with endothelial dysfunction in individuals without cardiovascular risk factors, similar to that observed in patients with hypertension, through a decrease in bioavailability of nitric oxide (NO), an important inflammatory mediator and a key regulator of vascular homeostasis.6 It has been suggested that the chronic exposure to pathogen-associated molecular patterns derived from periodontal pathogens produces low-grade systemic inflammation7,8 that may exacerbate concomitant inflammatory diseases (such as RA). Reciprocally, the immune dysregulation associated with RA and manifested as increased levels of circulating proinflammatory cytokines, such as IL-1, TNF-a, and IL-6, may increase susceptibility to CP in patients with RA9 given the necessary presence of bacterial challenge and proper local environment.

    The differentiation of peripheral blood mononuclear cells (PBMCs) into osteoclasts (OCs) is a key process to understanding bone loss associated with inflammatory conditions such as RA and CP.10 Cluster of differentiation 14�positive (CD14+) peripheral blood mononuclear phagocytes (PBMPs, a subpopulation of PBMCs) from healthy individuals can be differentiated into OCs in vitro in the presence of receptor activator of nuclear factor-kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Interestingly, the relative amount of CD14+ OC precursors is elevated in human peripheral blood from patients with psoriatic arthritis, another chronic inflammatory condition characterized by bone erosion mediated by OCs.11 Based on the concepts above, the aim of this study is to analyze the production of NO, chemokines, and pro- and anti-inflammatory cytokines by PBMCs obtained from patients with CP compared with those from healthy individuals. In addition, CD14+ PBMPs from both groups are also studied for their capacity to differentiate into OCs and resorb bone in vitro.