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

Nobuaki Sato, Naoyuki Takahashi, Koji Suda, Midori Nakamura, Mariko Yamaki, Tadashi Ninomiya, Yasuhiro Kobayashi, Haruhiko Takada, Kenichiro Shibata, Masahiro Yamamoto, Kiyoshi Takeda, Shizuo Akira, Toshihide Noguchi, Nobuyuki Udagawa

Research output: Contribution to journalArticlepeer-review

117 Citations (Scopus)


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-β (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-1α 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-κB 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-1α 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.

Original languageEnglish
Pages (from-to)601-611
Number of pages11
JournalJournal of Experimental Medicine
Issue number5
Publication statusPublished - 2004 Sep 6
Externally publishedYes


  • Bone resorption
  • Osteoporosis
  • Osteoprotegerin
  • Toll-like receptor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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