MyD88 but not TRIF is essential for osteoclastogenesis induced by lipopolysaccharide, diacyl lipopeptide, and IL-1alpha.
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.
Sato
Nobuaki
N
Dept. of Biochemistry, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri, Nagano 399-0781, Japan.
Takahashi
Naoyuki
N
Suda
Koji
K
Nakamura
Midori
M
Yamaki
Mariko
M
Ninomiya
Tadashi
T
Kobayashi
Yasuhiro
Y
Takada
Haruhiko
H
Shibata
Kenichiro
K
Yamamoto
Masahiro
M
Takeda
Kiyoshi
K
Akira
Shizuo
S
Noguchi
Toshihide
T
Udagawa
Nobuyuki
N
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology*; D015152:Blotting, Northern; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism; D001842:Bone and Bones / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins / Q000378:metabolism; D006579:Heterozygote; D007375:Interleukin-1 / Q000378:metabolism*; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D010024:Osteoporosis / Q000473:pathology; D053244:Osteoprotegerin; D010455:Peptides / Q000737:chemistry*; D016133:Polymerase Chain Reaction; D053245:RANK Ligand; D012333:RNA, Messenger / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B; D011956:Receptors, Cell Surface / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011971:Receptors, Immunologic / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction; D051193:Toll-Like Receptors; D014158:Transcription, Genetic
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000943:Antigens, Differentiation; D002352:Carrier Proteins; D006023:Glycoproteins; D007375:Interleukin-1; D008024:Ligands; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053244:Osteoprotegerin; D010455:Peptides; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D011971:Receptors, Immunologic; D018124:Receptors, Tumor Necrosis Factor; C470409:TICAM1 protein, human; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D051193:Toll-Like Receptors