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Signal transduction of RANK and Toll-like receptor in alveolar bone destruction

RANK和Toll样受体在牙槽骨破坏中的信号转导

基本信息

批准号：
15390565
负责人：
UDAGAWA Nobuyuki
金额：
$ 9.47万
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：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390565/
关键词：
LPS MyD88 TRIF TRAM IL-1 IL-6 bone marrow macrophage mouse リポ多糖破骨細胞骨芽細胞骨吸収骨形成自然免疫 TLR4

项目摘要

LPS is a potent stimulator of bone resorption in inflammatory diseases caused by bacteria. Bacterial lipoprotein/lipopeptides are also pathogen-specific molecular patterns. Toll-like receptor 4 (TLR4) is identified as the signaling receptor for LPS. The complex of TLR6 and TLR2 recognizes diacyl lipopeptide. The signaling cascade of TLR is similar to that of IL-1 receptors, because both TLR and IL-1receptors use MyD88 as a common signaling molecule. Toll-IL-1 receptor domain-containing adapter inducing interferon-γ (TRIF)-mediated signals are also shown to be involved in LPS-induced MyD88-independent pathway. Using MyD88-deficient (MyD88^<-/->) mice and TRIF-deficient (TRIF^<-/->) mice, we examined roles of MyD88 and TRIF in osteoclast differentiation and function. LPS, diacyl lipopeptide (DL) and IL-1 stimulated osteoclastogenesis in co-cultures of osteoblasts and hemopoietic cells obtained from TRIF^<-/-> mice but not MyD88^<-/-> mice. Bone marrow hemopoietic cells from MyD88^<-/-> m … More ice and TRIF^<-/-> mice similarly differentiated into osteoclasts in response to RANKL plus M-CSF. LPS, DL and IL-1 stimulated RANKL mRNA expression in TRIF^<-/-> osteoblasts but not MyD88^<-/-> osteoblasts, suggesting that only MyD88-mediated signal in osteoblasts was important for RANKL expression in response to those factors. This finding was particularly interesting, because both MyD88-dependent and TRIF-dependent pathways are essential for LPS-induced cytokine production in macrophages. Indeed, LPS failed to stimulate IL-6 production in TRIF^<-/-> bone marrow macrophages. But, LPS could stimulate IL-6 production in TRIF^<-/-> osteoblasts. LPS and IL-1 enhanced the survival of TRIF^<-/-> osteoclasts but not MyD88^<-/-> osteoclasts. DL did not support the survival of osteoclasts, because of the lack of TLR6 in osteoclasts. TRIF-related adaptor molecule (TRAM) was shown to be essentially involved in the TRIF-mediated signaling pathway. Interestingly, macrophages expressed both TRIF and TRAM mRNAs, while osteoblasts and osteoclasts expressed only TRIF mRNA. The fact that TRIF-mediated signals are not required for LPS-induced RANKL and IL-6 expression in osteoblasts and for osteoclast survival may be related to the lack of TRAM expression in osteoblasts and osteoclasts. Bone histomorphometry showed that MyD88^<-/-> mice exhibited low turnover osteoporosis with reduced bone resorption and formation. These results suggest that the MyD88-mediated signal is essential for the osteoclastogenesis and function induced by IL-1 and TLR ligands, and that MyD88 is physiologically involved in bone turnover. Less

在细菌引起的炎症性疾病中，LPS是骨吸收的有效刺激物。细菌脂蛋白/脂肽也是病原体特异性分子模式。Toll样受体4（TLR 4）被鉴定为LPS的信号传导受体。TLR 6和TLR 2的复合物识别二酰基脂肽。TLR的信号级联类似于IL-1受体的信号级联，因为TLR和IL-1受体都使用MyD 88作为共同的信号分子。含有Toll-IL-1受体结构域的衔接子诱导干扰素-γ（TRIF）介导的信号也显示参与LPS诱导的MyD 88非依赖性途径。使用MyD 88缺陷（MyD 88 ^<-/->）小鼠和TRIF缺陷（TRIF^<-/->）小鼠，我们检查了MyD 88和TRIF在破骨细胞分化和功能中的作用。LPS、二酰基脂肽（DL）和IL-1刺激从TRIF^<-/->小鼠而不是MyD 88 ^<-/->小鼠获得的成骨细胞和造血细胞的共培养物中的破骨细胞生成。来自MyD 88 ^<-/-> m的骨髓造血细胞 ...更多信息 Ice和TRIF^<-/->小鼠响应于RANKL加M-CSF类似地分化成破骨细胞。LPS、DL和IL-1刺激TRIF^<-/->成骨细胞中的RANKL mRNA表达，但不刺激MyD 88 ^<-/->成骨细胞，表明成骨细胞中只有MyD 88介导的信号对RANKL表达响应这些因子是重要的。这一发现特别有趣，因为MyD 88依赖性和TRIF依赖性途径对于巨噬细胞中LPS诱导的细胞因子产生至关重要。事实上，LPS未能刺激TRIF-β <-/->骨髓巨噬细胞中的IL-6产生。但LPS可刺激TRIF^<-/->成骨细胞产生IL-6。LPS和IL-1增强TRIF^<-/->破骨细胞的存活，但不增强MyD 88 ^<-/->破骨细胞的存活。DL不支持破骨细胞的存活，因为在破骨细胞中缺乏TLR 6。TRIF相关衔接分子（TRAM）被证明基本上参与TRIF介导的信号通路。有趣的是，巨噬细胞同时表达TRIF和TRAM mRNA，而成骨细胞和破骨细胞仅表达TRIF mRNA。事实上，TRIF介导的信号不是LPS诱导的RANKL和IL-6在成骨细胞中表达和破骨细胞存活所必需的，这可能与成骨细胞和破骨细胞中缺乏TRAM表达有关。骨组织形态计量学显示，MyD 88 ^<-/->小鼠表现出低转换性骨质疏松症，骨吸收和骨形成减少。这些结果表明，MyD 88介导的信号是必不可少的破骨细胞的生成和功能诱导的IL-1和TLR配体，MyD 88是生理上参与骨转换。少