Molecular mechanisms of the inhibitory effect of lipopolysaccharide (LPS) on osteoblast differentiation
Molecular mechanisms of the inhibitory effect of lipopolysaccharide (LPS) on osteoblast differentiation
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DOI：
10.1016/j.bbrc.2010.10.103
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发表时间：
2010-11-26
影响因子：
3.1
通讯作者：
Matsuguchi, Tetsuya
中科院分区：
文献类型：
--
作者：
Bandow, Kenjiro;Maeda, Aya;Matsuguchi, Tetsuya
成骨细胞表达Toll样受体4，并在脂多糖刺激下产生破骨细胞激活因子。最近报道，内毒素对成骨细胞向成骨细胞分化有抑制作用，但其分子机制尚不清楚。TLR4的下游信号是由包括髓系分化因子88(MyD88)在内的接头分子介导的，导致丝裂原激活的蛋白激酶(MAPKs)激活，如细胞外信号调节激酶(ERKs)，其激活需要上游的丝氨酸/苏氨酸激酶Cot/Tpl2分子来确定内毒素对成骨细胞的抑制作用。MyD88(-/-)和CoT/Tpl2(-/-)小鼠的原代成骨细胞的体外分化实验表明，在分化过程中，野生型和CoT/Tpl2(-/-)成骨细胞的基质矿化受到明显抑制，而MyD88(-/-)成骨细胞的基质矿化不受影响。在COT/Tpl2(-/-)成骨细胞分化的早期阶段，但在分化后期部分受损，因此，内毒素对成骨细胞分化的抑制作用是MyD88依赖的，而其对Cot/Tpl2的要求程度取决于分化阶段(C)2010 Elsevier Inc.保留所有权利
Osteoblasts express Toll like receptor (TLR) 4 and produce osteoclast-activating cytokines in response to the stimulation by lipopolysaccharide (LPS) It has recently been reported that LPS exerts an inhibitory effect on osteoblast differentiation into osteocytes However the molecular mechanisms of this inhibitory effect remain ambiguous The downstream signals of TLR4 are mediated by adaptor molecules including myeloid differentiation factor 88 (MyD88) leading to the activation of mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinases (ERKs) whose activation by LPS requires the upstream serine/threonine kinase Cot/Tpl2 To determine the signal molecules responsible for the inhibitory effects of LPS on osteoblast differentiation we examined the in vitro differentiation of the primary osteoblasts from myd88(-/-) and cot/tpl2(-/-) mice The matrix mineralization by the wild-type and cot/tpl2(-/-) osteoblasts was significantly inhibited by LPS whereas that of myd88(-/-) was not affected During differentiation LPS suppressed the mRNA expression of runt related transcription factor 2 (Runx2) osterix (Sp7) and activating transcription factor 4 (ATF4) in the wild-type but not in the myd88-/- osteoblasts The inhibitory effect of LPS on the mRNA expression of these transcription factors was absent in the early phase but partially impaired in the late phase of differentiation in the cot/tpl2(-/-) osteoblasts Thus the inhibitory effect of LPS on osteoblast differentiation is Myd88-dependent whereas the degree of its requirement for Cot/Tpl2 vanes depending on the differentiation phase (C) 2010 Elsevier Inc All rights reserved