title: Identification of a human peripheral blood monocyte subset that differentiates into osteoclasts.
abstract: 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.
authors.affiliation: Department of Medicine and Rheumatology, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Komano
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nanki
authors.forename: Kenji
authors.initials: K
authors.lastname: Hayashida
authors.forename: Ken
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Miyasaka
mesh_terms: 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
chemical_list: 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