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Muramyl Dipeptide Enhances Osteoclast Formation Induced by Lipopolysaccharide, IL-1, and TNF- through Nucleotide-Binding Oligomerization Domain 2-Mediated Signaling in Osteoblasts¹

Shuhua Yang^*, Naoyuki Takahashi, Teruhito Yamashita, Nobuaki Sato, Masahiro Takahashi^*, Makio Mogi^¶, Takashi Uematsu^*, Yasuhiro Kobayashi, Yuko Nakamichi, Kiyoshi Takeda^||, Shizuo Akira^#, Haruhiko Takada^**, Nobuyuki Udagawa^2, and Kiyofumi Furusawa^*

^* Department of Oral and Maxillofacial Surgery, Institute for Oral Science, and Department of Biochemistry, Matsumoto Dental University, Nagano, Japan; Department of Periodontology and ^¶ Department of Pharmacology, School of Dentistry, Aichi Gakuin University, Nagoya, Japan; ^|| Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; ^# Research Institute for Microbial Disease, Osaka University, Suita, Japan; and^** Department of Microbiology and Immunology, Tohoku University School of Dentistry, Sendai, Japan

Muramyl dipeptide (MDP) is the minimal essential structural unit responsible for the immunoadjuvant activity of peptidoglycan. As well as bone-resorbing factors such as 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) and PGE₂, LPS and IL-1 stimulate osteoclast formation in mouse cocultures of primary osteoblasts and hemopoietic cells. MDP alone could not induce osteoclast formation in the coculture, but enhanced osteoclast formation induced by LPS, IL-1, or TNF- but not 1,25(OH)₂D₃ or PGE₂. MDP failed to enhance osteoclast formation from osteoclast progenitors induced by receptor activator of NF-B ligand (RANKL) or TNF-. MDP up-regulated RANKL expression in osteoblasts treated with LPS or TNF- but not 1,25(OH)₂D₃. Osteoblasts expressed mRNA of nucleotide-binding oligomerization domain 2 (Nod2), an intracellular sensor of MDP, in response to LPS, IL-1, or TNF- but not 1,25(OH)₂D₃. Induction of Nod2 mRNA expression by LPS but not by TNF- in osteoblasts was dependent on TLR4 and MyD88. MDP also enhanced TNF--induced osteoclast formation in cocultures prepared from Toll/IL-1R domain-containing adapter protein (TIRAP)-deficient mice through the up-regulation of RANKL mRNA expression in osteoblasts, suggesting that TLR2 is not involved in the MDP-induced osteoclast formation. The depletion of intracellular Nod2 by small interfering RNA blocked MDP-induced up-regulation of RANKL mRNA in osteoblasts. LPS and RANKL stimulated the survival of osteoclasts, and this effect was not enhanced by MDP. These results suggest that MDP synergistically enhances osteoclast formation induced by LPS, IL-1, and TNF- through RANKL expression in osteoblasts, and that Nod2-mediated signals are involved in the MDP-induced RANKL expression in osteoblasts.

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The JI 2005 175: 1359-1360. [Full Text]  

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