Identification of a human peripheral blood monocyte subset that differentiates into osteoclasts

Arthritis Res Ther. 2006;8(5):R152. doi: 10.1186/ar2046.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Antigens, CD / metabolism
  • Arthritis, Rheumatoid / complications
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / pathology*
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • GPI-Linked Proteins
  • Humans
  • Integrin beta3 / genetics
  • Integrin beta3 / metabolism
  • Integrins / metabolism
  • Interleukin-6 / metabolism
  • Macrophage Colony-Stimulating Factor / pharmacology
  • Membrane Proteins
  • Monocytes / classification*
  • Monocytes / cytology*
  • Monocytes / metabolism
  • NF-kappa B / genetics
  • NFATC Transcription Factors / genetics
  • Osteoclasts / cytology*
  • Osteoporosis / complications
  • Osteoporosis / immunology
  • Osteoporosis / pathology*
  • Peptides, Cyclic / pharmacology
  • RANK Ligand / pharmacology
  • RNA, Small Interfering
  • Receptor, Macrophage Colony-Stimulating Factor / genetics
  • Receptors, Cell Surface / genetics
  • Receptors, IgG / metabolism
  • Receptors, Immunologic / genetics
  • Receptors, Vitronectin / metabolism
  • Synovial Membrane / immunology
  • Synovial Membrane / pathology
  • TNF Receptor-Associated Factor 6 / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • FCGR3B protein, human
  • GPI-Linked Proteins
  • Integrin beta3
  • Integrins
  • Interleukin-6
  • Membrane Proteins
  • NF-kappa B
  • NFATC Transcription Factors
  • NFATC1 protein, human
  • Peptides, Cyclic
  • RANK Ligand
  • RNA, Small Interfering
  • Receptors, Cell Surface
  • Receptors, IgG
  • Receptors, Immunologic
  • Receptors, Vitronectin
  • SIRPB1 protein, human
  • TNF Receptor-Associated Factor 6
  • TYROBP protein, human
  • Tumor Necrosis Factor-alpha
  • cyclo(arginyl-glycyl-aspartyl-phenylalanyl-valyl)
  • integrin alphavbeta1
  • Macrophage Colony-Stimulating Factor
  • Receptor, Macrophage Colony-Stimulating Factor
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases