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Establishment of periodontitis treatment method by inhibition of RANK-Toll like receptor signal

抑制RANK-Toll样受体信号治疗牙周炎方法的建立

基本信息

批准号：
17390497
负责人：
UDAGAWA Nobuyuki
金额：
$ 9.98万
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：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

MDP, the minimal essential structural unit responsible for the immunoadjuvant activity of peptidoglycans, is distributed ubiquitously in cell walls of both Gram-negative and-positive bacteria. MDP has been shown to exert diverse biological effects on immunocompetent cells. We have shown that injection of MDP into mice resulted in endotoxin hypersensitivity : enhanced production of TNF-α and lethal shock upon challenge injection of LPS. We also showed that MDP synergistically enhanced LPS-induced proinflammatory cytokine production in human monocytic cells. Recently, it was proposed that nucleotide-binding oligomerization domain (Nod) 2, a member of the Apaf1/Nod protein family, is an intracellular sensor of MDP. Nod2 consists of an N-terminal caspase-recruitment domain, a centrally located nucleotide-binding domain and C-terminal leucine-rich repeats, and acts as a signal-transducing adaptor. Nod2 expression is enhanced by proinflammatory cytokines and LPS. 1 α,25(OH)2D3, PGE2, LPS and … More IL-1 a stimulate osteoclast formation in mouse cocultures of osteoblasts and hemopoietic cells. MDP alone could not induce osteoclast formation in the coculture, but enhanced osteoclast formation induced by LPS, IL-1α or TNF-α but not 1 α,25(OH)2D3 or PGE2. MDP failed to enhance osteoclast formation from osteoclast progenitors induced by RANKL or TNF-α. MDP up-regulated RANKL expression in osteoblasts treated with LPS or TNF-α but not 1 α,25(OH)2D3. Osteoblasts expressed mRNA of Nod2 in response to LPS, IL-1α or TNF-α but not 1 α,25(OH)2D3. Induction of Nod2 mRNA expression by LPS but not by TNF-α in osteoblasts was dependent on TLR4 and MyD88. 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-1α and TNF-a through RANKL expression in osteoblasts, and that Nod2-mediated signals are involved in the MDP-induced RANKL expression in osteoblasts. Less

MDP 是负责肽聚糖免疫佐剂活性的最小基本结构单元，广泛分布于革兰氏阴性和阳性细菌的细胞壁中。 MDP 已被证明对免疫活性细胞产生多种生物学效应。我们已经证明，向小鼠注射 MDP 会导致内毒素过敏：TNF-α 的产生增加，并且在注射 LPS 后会导致致死性休克。我们还表明，MDP 可以协同增强人单核细胞中 LPS 诱导的促炎细胞因子的产生。最近，有人提出，Apaf1/Nod 蛋白家族的成员核苷酸结合寡聚化结构域 (Nod) 2 是 MDP 的细胞内传感器。 Nod2 由 N 端 caspase 招募结构域、位于中心的核苷酸结合结构域和 C 端富含亮氨酸的重复序列组成，并充当信号转导接头。促炎细胞因子和 LPS 增强 Nod2 表达。 1 α,25(OH)2D3、PGE2、LPS 和…更多 IL-1 a 在小鼠成骨细胞和造血细胞共培养物中刺激破骨细胞形成。单独的MDP不能在共培养物中诱导破骨细胞形成，但增强LPS、IL-1α或TNF-α诱导的破骨细胞形成，但不增强1α、25(OH)2D3或PGE2诱导的破骨细胞形成。 MDP 未能增强 RANKL 或 TNF-α 诱导的破骨细胞祖细胞的破骨细胞形成。 MDP 上调用 LPS 或 TNF-α 处理的成骨细胞中的 RANKL 表达，但不上调 1 α,25(OH)2D3 处理的成骨细胞中的 RANKL 表达。成骨细胞响应 LPS、IL-1α 或 TNF-α 而表达 Nod2 mRNA，但不表达 1 α,25(OH)2D3。在成骨细胞中，LPS（而非 TNF-α）诱导 Nod2 mRNA 表达依赖于 TLR4 和 MyD88。小干扰RNA消除细胞内Nod2可阻断MDP诱导的成骨细胞中RANKL mRNA的上调。 LPS 和 RANKL 刺激破骨细胞的存活，而 MDP 并未增强这种效果。这些结果表明，MDP通过成骨细胞中RANKL的表达协同增强LPS、IL-1α和TNF-a诱导的破骨细胞形成，并且Nod2介导的信号参与MDP诱导的成骨细胞中的RANKL表达。较少的

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The mechanism of coupling between bone resorption and bone formation.

骨吸收与骨形成的耦合机制。

DOI：
发表时间：
2006
期刊：
J Oral Biosciences 48・(3)
影响因子：
0
作者：
Nakamichi Y et al.;Tsukiyama K et al.;Itoh S et al.;Yamamoto Y et al.;Udagawa N et al.
通讯作者：
Udagawa N et al.

Prostaglandin E2 strongly inhibits human osteoclast formation

DOI：
10.1210/en.2005-0451
发表时间：
2005-12-01
期刊：
ENDOCRINOLOGY
影响因子：
4.8
作者：
Take, I;Kobayashi, Y;Takahashi, N
通讯作者：
Takahashi, N

Prostaglandin E2 receptors EP2 and EP4 are down-regulated during differentiation of mouse osteoclasts from their precursors

DOI：
10.1074/jbc.m500926200
发表时间：
2005-06-24
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Kobayashi, Y;Take, I;Takahashi, N
通讯作者：
Takahashi, N

Osteoblasts provide a suitable microenvironment for the action of receptor activator of NF-kB ligand

成骨细胞为 NF-kB 配体受体激活剂的作用提供合适的微环境

DOI：
发表时间：
2006
期刊：
Endocrinology 147
影响因子：
0
作者：
Yohei Yamamoto;et. al.
通讯作者：
et. al.

Osteoblasts provide a suitable microenvironment for the action of receptor activator of NF-κB ligand

成骨细胞为 NF-κB 配体受体激活剂的作用提供合适的微环境

DOI：
发表时间：
2006
期刊：
Endocrinology (In Press)
影响因子：
0
作者：
Ohno-Matsui K;Ichinose S;Nakahama K;Yoshida T;Kojima A;Mochizuki M;Morita I;Yamamoto Y.
通讯作者：
Yamamoto Y.