Muramyl dipeptide enhances osteoclast formation induced by lipopolysaccharide, IL-1α, and TNF-α through nucleotide-binding oligomerization domain 2-mediated signaling in osteoblasts

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, Kiyofumi Furusawa

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61 Citations (Scopus)

Abstract

Muramyl dipeptide (MDP) is the minimal essential structural unit responsible for the immunoadjuvant activity of peptidoglycan. As well as bone-resorbing factors such as 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) and PGE2, LPS and IL-1α 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-1α, or TNF-α but not 1α,25(OH)2D3 or PGE2. MDP failed to enhance osteoclast formation from osteoclast progenitors induced by receptor activator of NF-κB ligand (RANKL) or TNF-α. MDP up-regulated RANKL expression in osteoblasts treated with LPS or TNF-α but not 1α,25(OH)2D3. Osteoblasts expressed mRNA of nucleotide-binding oligomerization domain 2 (Nod2), an intracellular sensor of MDP, in response to LPS, IL-1α, or TNF-α but not 1α,25(OH)2D3. Induction of Nod2 mRNA expression by LPS but not by TNF-α in osteoblasts was dependent on TLR4 and MyD88. MDP also enhanced TNF-α-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-1α, and TNF-α through RANKL expression in osteoblasts, and that Nod2-mediated signals are involved in the MDP-induced RANKL expression in osteoblasts.

Original languageEnglish
Pages (from-to)1956-1964
Number of pages9
JournalJournal of Immunology
Volume175
Issue number3
DOIs
Publication statusPublished - 2005 Aug 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Yang, S., Takahashi, N., Yamashita, T., Sato, N., Takahashi, M., Mogi, M., Uematsu, T., Kobayashi, Y., Nakamichi, Y., Takeda, K., Akira, S., Takada, H., Udagawa, N., & Furusawa, K. (2005). Muramyl dipeptide enhances osteoclast formation induced by lipopolysaccharide, IL-1α, and TNF-α through nucleotide-binding oligomerization domain 2-mediated signaling in osteoblasts. Journal of Immunology, 175(3), 1956-1964. https://doi.org/10.4049/jimmunol.175.3.1956