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Analysis of signal transduction of osteoclast differentiation factor (RANKL) in alveolar bone destruction

破骨细胞分化因子（RANKL）在牙槽骨破坏中的信号转导分析

基本信息

批准号：
13470394
负责人：
UDAGAWA Nobuyuki
金额：
$ 9.28万
依托单位：
Matsumoto Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470394/
关键词：
Osteoclasts Lipopolysaccharide Lipopeptide IL-1 MyD88 RANKL OPG Toll-like receptor マクロファージリポ多糖 OPG TNF IL-1

项目摘要

Lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria, is proposed to be a potent stimulator of bone resorption in inflammatory diseases caused by bacreria. Bacterial lipoprotein/lipopeptides are also pathogen-specific molecular patterns. Recently, toll-like receptor 4 (TLR4) was identified as the signaling receptor for LPS. In addition, TLR6 associate with TLR2, and the complex of TLR6 and TLR2 recognizes diacylated mycoplasmal lipopeptides. The signaling cascade of TLR is believed to be similar to that of IL-1 receptors (IL- 1R), because both TLR and IL-1R use myeloid differentiation factor 88 (MyD88) as a common cytoplasmic signaling molecule. However, accumulating evidence also demonstrates the existence of MyD88-independent pathways, which may explain unique biological responses of individual TLR and IL-1R. Using MyD88-deficient (-/-) mice, we explored the involvement of MyD88-mediated signals in osteoclast formation. LPS, synthetic lipopept … More ide (FSL-1), IL-1a and 1.25(OH)_2D_3 all stimulated osteoclast formation in co-cultures of primary osteoblasts and bone marrow cells obtained from wild-type mice. Osteoprotegerin, a decoy receptor of RANKL, completely inhibited the osteoclast formation in the co-culture. In contrasts, LPS, lipopeptide and IL-1a failed to induce the osteoclast formation in the co-culture of Myd88 (-/-) mice-derived osteoblasts and bone marrow cells, though 1.25(OH)_2D_3 stimulated osteoclast formation even in the MyD88 (-/-) co-culture. RT-PCR analysis showed that primary osteoblasts obtained from both wild type and MyD88 (-/-) mice similarly expressed TLR2, TLR4, TLR6 and IL-1R mRNAs. LPS, lipopeptide and IL-1a stimulated expression of RANKL mRNA within 24 hr in primary osteoblasts obtained from wild-type mice but not in those from MyD88 (-/-) mice. Similarly, LPS and IL-1a stimulated phosphorylation of ERK in wild-type osteoblasts but not MyD88 (-/-) osteoblasts. Hemopoietic cells obtained from MyD88 (-/-) mice and those from wild-type mice similarly differentiated into osteoclasts within 3 days in response to RANKL and M-CSF. These results suggest that the MyD88-mediated signaling pathway is essentially involved in osteoclast formation induced by LPS, lipopeptide and IL-1a through the RANKL expression by osteoblasts. Less

脂多糖（LPS）是革兰氏阴性菌外膜的主要成分，被认为是由细菌引起的炎症性疾病中骨吸收的有效刺激剂。细菌脂蛋白/脂肽也是病原体特异性分子模式。最近，Toll样受体4（TLR 4）被鉴定为LPS的信号受体。另外，TLR 6与TLR 2结合，TLR 6和TLR 2的复合物识别二酰化支原体脂肽。TLR的信号级联被认为与IL-1受体（IL-1 R）的信号级联相似，因为TLR和IL-1 R都使用髓样分化因子88（MyD 88）作为共同的细胞质信号分子。然而，越来越多的证据也表明存在MyD 88非依赖性途径，这可能解释个体TLR和IL-1 R的独特生物学反应。使用MyD 88缺陷（-/-）小鼠，我们探索了MyD 88介导的信号在破骨细胞形成中的参与。LPS，合成脂肽 ...更多信息 IDE（FSL-1）、IL-1a和1.25（OH）_2D_3均能刺激原代成骨细胞和野生型小鼠骨髓细胞共培养中破骨细胞的形成。RANKL的诱骗受体Osteoprotegerin可完全抑制破骨细胞的形成。LPS、脂肽和IL-1a不能诱导Myd 88（-/-）鼠源性成骨细胞和骨髓细胞共培养时破骨细胞的形成，而1.25（OH）_2D_3能促进Myd 88（-/-）鼠源性成骨细胞和骨髓细胞共培养时破骨细胞的形成。RT-PCR分析显示，从野生型和MyD 88（-/-）小鼠获得的原代成骨细胞相似地表达TLR 2、TLR 4、TLR 6和IL-1 R mRNA。LPS、脂肽和IL-1a在24小时内刺激野生型小鼠的原代成骨细胞中RANKL mRNA的表达，但在MyD 88（-/-）小鼠的原代成骨细胞中没有。类似地，LPS和IL-1a刺激野生型成骨细胞中ERK的磷酸化，但不刺激MyD 88（-/-）成骨细胞。从MyD 88（-/-）小鼠和野生型小鼠获得的造血细胞在RANKL和M-CSF的作用下在3天内分化为破骨细胞。这些结果表明，MyD 88介导的信号通路基本上参与了LPS、脂肽和IL-1a通过成骨细胞表达RANKL诱导的破骨细胞形成。少