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

LPS是由细菌引起的炎症性疾病中骨骼分辨率的潜在刺激剂。细菌脂蛋白/脂肪肽也是病原体特异性分子模式。 Toll样受体4（TLR4）被鉴定为LPS的信号受体。 TLR6和TLR2的复合物识别二酰基脂肽。 TLR的信号传导级联反应与IL-1受体的信号级联相似，因为TLR和IL-1受体使用MyD88作为常见信号分子。 Toll-IL-1受体结构域的辅助转络诱导的干扰素-γ（TRIF）介导的信号也被证明与LPS诱导的MYD88独立途径有关。使用MyD88缺乏（MyD88^< - / - >）小鼠和Trif缺乏症（Trif^< - / - >）小鼠，我们检查了MyD88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在成骨细胞和从TRIF^< - / - >小鼠中获得的成骨细胞和血压细胞的共培养中刺激破骨细胞生成。 Myd88^< - / - > m的骨髓肢体细胞……更多的冰和Trif^< - / - >小鼠类似地分化为破骨细胞，以响应RANKL加M-CSF。 LPS，DL和IL-1在TRIF^< - / - >成骨细胞中刺激了RANKL mRNA表达，但不是MyD88^< - / - >成骨细胞，这表明仅在成骨细胞中仅MyD88介导的信号对于对这些因素的响应而言，对rankl表达很重要。这一发现特别有趣，因为MyD88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。实际上，LP未能刺激Trif^< - / - >骨髓巨噬细胞中的IL-6产生。但是，LP可以刺激Trif^< - / - >成骨细胞中的IL-6产生。 LPS和IL-1增强了Trif^< - / - >破骨细胞的存活，而不是MyD88^< - / - >破骨骨质骨化。由于破骨细胞缺乏TLR6，DL不支持破骨细胞的存活。与TRIF相关的适配器分子（TRAM）证明与TRIF介导的信号通路基本上有关。有趣的是，巨噬细胞同时表达了TRIF和电车mRNA，而成骨细胞和破骨细胞仅表示TRIF mRNA。在成骨细胞中LPS诱导的RANKL和IL-6表达不需要TRIF介导的信号，而对于骨细胞存活，这一事实可能与成骨细胞和破骨细胞中缺乏Tram表达有关。骨骼组形态测定法表明，MyD88^< - / - >小鼠暴露于低周转骨质疏松症，骨骼分辨率和形成减少。这些结果表明，MyD88介导的信号对于由IL-1和TLR配体诱导的破骨细胞生成和功能至关重要，并且MYD88实际上参与了骨转换。较少的