MyD88 but not TRIF is essential for osteoclastogenesis induced by lipopolysaccharide, diacyl lipopeptide, and IL-1alpha

J Exp Med. 2004 Sep 6;200(5):601-11. doi: 10.1084/jem.20040689.

Abstract

Myeloid differentiation factor 88 (MyD88) plays essential roles in the signaling of the Toll/interleukin (IL)-1 receptor family. Toll-IL-1 receptor domain-containing adaptor inducing interferon-beta (TRIF)-mediated signals are involved in lipopolysaccharide (LPS)-induced MyD88-independent pathways. Using MyD88-deficient (MyD88-/-) mice and TRIF-deficient (TRIF-/-) mice, we examined roles of MyD88 and TRIF in osteoclast differentiation and function. LPS, diacyl lipopeptide, and IL-1alpha stimulated osteoclastogenesis in cocultures of osteoblasts and hemopoietic cells obtained from TRIF-/- mice, but not MyD88-/- mice. These factors stimulated receptor activator of nuclear factor-kappaB ligand mRNA expression in TRIF-/- osteoblasts, but not MyD88-/- osteoblasts. LPS stimulated IL-6 production in TRIF-/- osteoblasts, but not TRIF-/- macrophages. LPS and IL-1alpha enhanced the survival of TRIF-/- osteoclasts, but not MyD88-/- osteoclasts. Diacyl lipopeptide did not support the survival of osteoclasts because of the lack of Toll-like receptor (TLR)6 in osteoclasts. Macrophages expressed both TRIF and TRIF-related adaptor molecule (TRAM) mRNA, whereas osteoblasts and osteoclasts expressed only TRIF mRNA. Bone histomorphometry showed that MyD88-/- mice exhibited osteopenia with reduced bone resorption and formation. These results suggest that the MyD88-mediated signal is essential for the osteoclastogenesis and function induced by IL-1 and TLR ligands, and that MyD88 is physiologically involved in bone turnover.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport / physiology*
  • Animals
  • Antigens, Differentiation / physiology*
  • Blotting, Northern
  • Blotting, Western
  • Bone Marrow Cells / metabolism
  • Bone and Bones / pathology
  • Carrier Proteins / metabolism
  • Cell Differentiation
  • Coculture Techniques
  • Dose-Response Relationship, Drug
  • Glycoproteins / metabolism
  • Heterozygote
  • Interleukin-1 / metabolism*
  • Ligands
  • Lipopolysaccharides / metabolism*
  • Macrophages / metabolism
  • Male
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Biological
  • Myeloid Differentiation Factor 88
  • Osteoblasts / metabolism
  • Osteoclasts / cytology*
  • Osteoclasts / metabolism
  • Osteoporosis / pathology
  • Osteoprotegerin
  • Peptides / chemistry*
  • Polymerase Chain Reaction
  • RANK Ligand
  • RNA, Messenger / metabolism
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Cell Surface / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Immunologic / physiology*
  • Receptors, Tumor Necrosis Factor
  • Signal Transduction
  • Toll-Like Receptors
  • Transcription, Genetic

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Antigens, Differentiation
  • Carrier Proteins
  • Glycoproteins
  • Interleukin-1
  • Ligands
  • Lipopolysaccharides
  • MYD88 protein, human
  • Membrane Glycoproteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Osteoprotegerin
  • Peptides
  • RANK Ligand
  • RNA, Messenger
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Cell Surface
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Immunologic
  • Receptors, Tumor Necrosis Factor
  • TICAM1 protein, human
  • TNFRSF11A protein, human
  • TNFRSF11B protein, human
  • TNFSF11 protein, human
  • Tnfrsf11a protein, mouse
  • Tnfrsf11b protein, mouse
  • Tnfsf11 protein, mouse
  • Toll-Like Receptors