Abstract
We investigated the relationships among M1 monocytes, M2 monocytes, osteoclast (OC) differentiation ability, and clinical characteristics in patients with rheumatoid arthritis (RA). Peripheral blood mononuclear cells (PBMCs) were isolated from RA patients and healthy donors, and we then investigated the number of M1 monocytes or M2 monocytes by fluorescence-activated cell sorting. We also obtained and cultured CD14-positive cells from PBMCs from RA patients and healthy donors to investigate OC differentiation in vitro. Forty RA patients and 20 healthy donors were included. Twenty-two patients (55%) were anticitrullinated protein antibody (ACPA) positive. The median M1/M2 ratio was 0.59 (0.31-1.11, interquartile range). There were no significant differences between the RA patients and healthy donors. There was a positive correlation between the M1/M2 ratio and the differentiated OC number in vitro in RA patients (ρ = 0.81, p < 0.001). The ACPA-positive patients had significantly higher M1/M2 ratios in vivo (p = 0.028) and significantly greater numbers of OCs in vitro (p = 0.005) than the ACPA-negative patients. Multivariable regression analysis revealed that the M1/M2 ratio was the sole significant contribution factor to in vitro osteoclastogenesis. RA patients with M1/M2 ratios >1 (having relatively more M1 monocytes) had higher C-reactive protein and erythrocyte sedimentation rates than RA patients with M1/M2 ratios ≤1. M1-dominant monocytes in vitro produced higher concentrations of interleukin-6 upon stimulation with lipopolysaccharide than M2 monocytes. M1/M2 monocytes imbalance strongly contributes to osteoclastogenesis of RA patients. Our findings cast M1 and M2 monocyte subsets in a new light as a new target of treatments for RA to prevent progression of osteoclastic bone destruction.
Highlights
Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis and is characterized by inflammation and matrix destruction of bone and cartilage [1]
We investigated the relationships among M1 monocytes, M2 monocytes, osteoclast (OC) differentiation ability, and clinical characteristics in patients with rheumatoid arthritis (RA)
Peripheral blood mononuclear cells (PBMCs) were isolated from RA patients and healthy donors, and we investigated the number of M1 monocytes or M2 monocytes by fluorescence-activated cell sorting
Summary
Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis and is characterized by inflammation and matrix destruction of bone and cartilage [1]. OCs are differentiated from monocytes and macrophages through the stimulation of receptor activator for nuclear factor kappa-B ligand (RANKL) in the presence of macrophage colony-stimulating factor (M-CSF) [4]. Monocytes can differentiate into proinflammatory, microbicidal M1 macrophage, or anti-inflammatory M2 macrophage subtypes [6]. Macrophages are activated toward M1 macrophages by infectious microorganism-related molecules such as lipopolysaccharides (LPSs) and by inflammatory cytokines such as interferon-γ [7]. M1 macrophages can produce toxic effector molecules such as reactive oxygen species and nitric monoxide, and inflammatory cytokines such as interleukin (IL)-1β, tumor necrosis factor (TNF), and IL-6 [8]. M2 macrophage polarization is observed in response to Th2-related cytokines such as IL-4 and IL-13 [9]. Anti-inflammatory cytokines such as IL-10 and TGF-β are associated with M2 macrophage polarization [10]
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