Muramyl dipeptide enhances osteoclast formation induced by lipopolysaccharide, IL-1 alpha, and TNF-alpha through nucleotide-binding oligomerization domain 2-mediated signaling in osteoblasts.
Muramyl dipeptide enhances osteoclast formation induced by lipopolysaccharide, IL-1 alpha, and TNF-alpha through nucleotide-binding oligomerization domain 2-mediated signaling in osteoblasts.
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发表时间：
2005
影响因子：
4.4
通讯作者：
Shuhua Yang;N. Takahashi;T. Yamashita;N. Sato;Masahiro Takahashi;M. Mogi;T. Uematsu;Yasuhiro Kobayashi;Yuko Nakamichi;K. Takeda;S. Akira;H. Takada;N. Udagawa;K. Furusawa
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文献类型：
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作者：
Shuhua Yang;N. Takahashi;T. Yamashita;N. Sato;Masahiro Takahashi;M. Mogi;T. Uematsu;Yasuhiro Kobayashi;Yuko Nakamichi;K. Takeda;S. Akira;H. Takada;N. Udagawa;K. Furusawa
胞壁酰二肽（MDP）是肽聚糖免疫佐剂活性的最小必需结构单元。在小鼠原代成骨细胞和造血细胞的共培养物中，除了骨吸收因子如1 α，25-二羟维生素D3（1 α，25（OH）2D 3）和PGE 2外，LPS和IL-1 α也刺激破骨细胞的形成。MDP单独不能诱导破骨细胞的形成，但可增强LPS、IL-1 α或TNF-α诱导的破骨细胞形成，但对1 α、25（OH）2D 3或PGE 2无影响。MDP未能增强由NF-κ B配体受体激活剂（RANKL）或TNF-α诱导的破骨细胞祖细胞形成破骨细胞。MDP上调LPS或TNF-α处理的成骨细胞中RANKL的表达，但不上调1 α，25（OH）2D 3。成骨细胞表达核苷酸结合寡聚化结构域2（Nod 2）的mRNA，Nod 2是MDP的细胞内传感器，对LPS，IL-1 α或TNF-α有反应，但对1 α，25（OH）2D 3无反应。LPS诱导成骨细胞Nod 2 mRNA表达依赖于TLR 4和MyD 88，而TNF-α不诱导成骨细胞Nod 2 mRNA表达。MDP还通过上调成骨细胞中RANKL mRNA的表达，增强了Toll/IL-1 R结构域衔接蛋白（TIRAP）缺陷小鼠制备的共培养物中TNF-α诱导的破骨细胞形成，表明TLR 2不参与MDP诱导的破骨细胞形成。通过小干扰RNA去除细胞内Nod 2阻断了成骨细胞中MDP诱导的RANKL mRNA上调。LPS和RANKL刺激破骨细胞的存活，并且这种作用不被MDP增强。这些结果表明，MDP协同增强破骨细胞形成诱导的LPS，IL-1 α，TNF-α通过RANKL表达成骨细胞，和Nod 2介导的信号参与MDP诱导RANKL表达成骨细胞。
Muramyl dipeptide (MDP) is the minimal essential structural unit responsible for the immunoadjuvant activity of peptidoglycan. As well as bone-resorbing factors such as 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) and PGE2, LPS and IL-1alpha 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-1alpha, or TNF-alpha but not 1alpha,25(OH)2D3 or PGE2. MDP failed to enhance osteoclast formation from osteoclast progenitors induced by receptor activator of NF-kappaB ligand (RANKL) or TNF-alpha. MDP up-regulated RANKL expression in osteoblasts treated with LPS or TNF-alpha but not 1alpha,25(OH)2D3. Osteoblasts expressed mRNA of nucleotide-binding oligomerization domain 2 (Nod2), an intracellular sensor of MDP, in response to LPS, IL-1alpha, or TNF-alpha but not 1alpha,25(OH)2D3. Induction of Nod2 mRNA expression by LPS but not by TNF-alpha in osteoblasts was dependent on TLR4 and MyD88. MDP also enhanced TNF-alpha-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-1alpha, and TNF-alpha through RANKL expression in osteoblasts, and that Nod2-mediated signals are involved in the MDP-induced RANKL expression in osteoblasts.