Identification of a human peripheral blood monocyte subset that differentiates into osteoclasts.
Increased bone resorption mediated by osteoclasts causes various diseases such as osteoporosis and bone erosion in rheumatoid arthritis (RA). Osteoclasts are derived from the monocyte/macrophage lineage, but the precise origin remains unclear. In the present study, we show that the purified CD16- human peripheral blood monocyte subset, but not the CD16+ monocyte subset, differentiates into osteoclast by stimulation with receptor activator of NF-kappaB ligand (RANKL) in combination with macrophage colony-stimulating factor (M-CSF). Integrin-beta3 mRNA and the integrin-alpha(v)beta3 heterodimer were only expressed on CD16- monocytes, when they were stimulated with RANKL + M-CSF. Downregulation of beta3-subunit expression by small interfering RNA targeting beta3 abrogated osteoclastogenesis from the CD16- monocyte subset. In contrast, the CD16+ monocyte subset expressed larger amounts of tumor necrosis factor alpha and IL-6 than the CD16- subset, which was further enhanced by RANKL stimulation. Examination of RA synovial tissue showed accumulation of both CD16+ and CD16- macrophages. Our results suggest that peripheral blood monocytes consist of two functionally heterogeneous subsets with distinct responses to RANKL. Osteoclasts seem to originate from CD16- monocytes, and integrin beta3 is necessary for osteoclastogenesis. Blockade of accumulation and activation of CD16- monocytes could therefore be a beneficial approach as an anti-bone resorptive therapy, especially for RA.
Komano
Yukiko
Y
Department of Medicine and Rheumatology, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
Nanki
Toshihiro
T
Hayashida
Kenji
K
Taniguchi
Ken
K
Miyasaka
Nobuyuki
N
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000276:immunology / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D058851:GPI-Linked Proteins; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008565:Membrane Proteins; D009000:Monocytes / Q000145:classification* / Q000166:cytology* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics; D050778:NFATC Transcription Factors / Q000235:genetics; D010010:Osteoclasts / Q000166:cytology*; D010024:Osteoporosis / Q000150:complications / Q000276:immunology / Q000473:pathology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D053245:RANK Ligand / Q000494:pharmacology; D034741:RNA, Small Interfering; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D017452:Receptors, IgG / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics; D019030:Receptors, Vitronectin / Q000378:metabolism; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D039661:Integrin beta3; D016023:Integrins; D015850:Interleukin-6; D008565:Membrane Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D010456:Peptides, Cyclic; D053245:RANK Ligand; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D019030:Receptors, Vitronectin; C501921:SIRPB1 protein, human; D048029:TNF Receptor-Associated Factor 6; C110546:TYROBP protein, human; D014409:Tumor Necrosis Factor-alpha; C092113:cyclo(arginyl-glycyl-aspartyl-phenylalanyl-valyl); C094340:integrin alphavbeta1; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases