The Journal of Experimental Medicine
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Published 7 September 2004. doi:10.1084/jem.20040689
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 5, 601-611
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MyD88 But Not TRIF Is Essential for Osteoclastogenesis Induced by Lipopolysaccharide, Diacyl Lipopeptide, and IL-1{alpha}

Nobuaki Sato1,4, Naoyuki Takahashi2, Koji Suda5, Midori Nakamura3, Mariko Yamaki2, Tadashi Ninomiya2, Yasuhiro Kobayashi2, Haruhiko Takada6, Kenichiro Shibata7, Masahiro Yamamoto8, Kiyoshi Takeda9, Shizuo Akira8, Toshihide Noguchi4, and Nobuyuki Udagawa1

1 Department of Biochemistry, Matsumoto Dental University, Nagano 399-0781, Japan
2 Institute for Oral Science, Matsumoto Dental University, Nagano 399-0781, Japan
3 Department of Pediatric Dentistry, Matsumoto Dental University, Nagano 399-0781, Japan
4 Department of Periodontology, School of Dentistry, Aichi Gakuin University, Nagoya 464-8651, Japan
5 Department of Biochemistry, School of Dentistry, Showa University, Tokyo 142-8555, Japan
6 Department of Microbiology and Immunology, Tohoku University School of Dentistry, Sendai, 980-8575, Japan
7 Department of Oral Pathobiological Science, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan
8 Research Institute for Microbial Diseases, Osaka University, Suita 565-0871, Japan
9 Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan

Address correspondence to Nobuyuki Udagawa, Dept. of Biochemistry, Matsumoto Dental University, 1780 Gobara, Hiro-oka, Shiojiri, Nagano 399-0781, Japan. Phone: 81-263-51-2072; Fax: 81-263-51-2223; email: udagawa{at}po.mdu.ac.jp

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-ß (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-1{alpha} 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-{kappa}B 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-1{alpha} 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.

Key Words: Toll-like receptor • osteoprotegerin • RANKL • bone resorption • osteoporosis

Abbreviations used in this paper: ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; M-CSF, macrophage CSF; MEK, MAPK/ERK kinase; MyD88, myeloid differentiation factor 88; MyD88–/–, MyD88-deficient; OPG, osteoprotegerin; PKC, protein kinase C; RANK, receptor activator of NF-{kappa}B; RANKL, RANK ligand; TIR, Toll/IL-1 receptor; TLR, Toll-like receptor; TRAM, TRIF-related adaptor molecule; TRAM–/–, TRAM-deficient; TRAP, tartrate-resistant acid phosphatase; TRIF, TIR domain-containing adaptor-inducing IFN-ß; TRIF–/–, TRIF-deficient.


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