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是负责肽聚糖免疫辅助活性的最小必需结构单元，无处不在地分布在革兰氏阴性和阳性细菌的细胞壁中。 MDP已显示出对免疫能力细胞的潜水生物学作用。我们已经表明，将MDP注射到小鼠中导致内毒素超敏反应：在挑战LPS挑战时，TNF-α的产生和致命的休克产生增强。我们还表明，MDP合成增强了LPS诱导的人单核细胞中促炎细胞因子的产生。最近，有人提出，APAF1/NOD蛋白质家族的成员是MDP的细胞内传感器，核震荡结构寡聚结构域（NOD）2是MDP的细胞内传感器。 NOD2由N末端caspase-recruitment域组成，该结构域是一个位于中央的核刺结构结构域和富含C末端亮氨酸的重复序列，并充当信号传递适配器。 NOD2表达通过促炎细胞因子和LPS增强。 1α，25（OH）2d3，pGE2，LPS和…更多IL-1 A刺激的骨细胞形成在成骨细胞和血压细胞的小鼠共培养物中。单独的MDP不能在共培养中诱导破骨细胞的形成，而是增强了由LPS，IL-1α或TNF-α诱导的破骨细胞形成，而不是1α，25（OH）2D3或PGE2。 MDP无法增强由RANKL或TNF-α诱导的破骨细胞祖细胞的破骨细胞形成。 MDP在用LPS或TNF-α处理的成骨细胞中上调RANKL表达，而不是1α，25（OH）2d3。成骨细胞响应于LPS，IL-1α或TNF-α而表达NOD2的mRNA，而不是1α，25（OH）2d3。通过LPS诱导NOD2 mRNA表达，而不是TNF-α在成骨细胞中诱导的诱导取决于TLR4和MYD88。小型干扰RNA通过细胞内NOD2的部署阻断了MDP诱导的成骨细胞中RANKL mRNA的上调。 LPS和RANKL刺激了破骨细胞的存活，MDP并未增强这种作用。这些结果表明，MDP协同增强了成骨细胞中LPS，IL-1α和TNF-A诱导的破骨细胞形成，并且在成骨细胞中，MDP诱导的RANKL表达参与了成骨细胞的NOD2介导的信号。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.

Gastric inhibitory polypeptide as an endogenous factor promoting new bone formation following food ingestion.

胃抑制多肽作为促进食物摄入后新骨形成的内源性因子。

DOI：
发表时间：
2006
期刊：
Mol Endocrinol 20・(7)
影响因子：
0
作者：
Nakamichi Y et al.;Tsukiyama K et al.
通讯作者：
Tsukiyama K et al.

Transcytosis of calcium from bone by osteoclast-like cells evidenced by direct visualization of calcium in cells.

破骨细胞样细胞对骨中钙的转胞吞作用通过细胞中钙的直接可视化得到证实。

DOI：
发表时间：
2005
期刊：
Arch Biochem Biophys 440
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.;Okumura S et al.;Nakamichi Y et al.;Tsukiyama K et al.;Itoh S et al.;Yamamoto Y et al.;Udagawa N et al.;Okumura S et al.;Takahashi N et al.;Yamaki M
通讯作者：
Yamaki M

Nurse-like cells from patients with rheumatoid arthritis support survival of osteoclast precursors via macrophage-colony stimulating factor production.

来自类风湿性关节炎患者的护士样细胞通过巨噬细胞集落刺激因子的产生支持破骨细胞前体的存活。

DOI：
发表时间：
2005
期刊：
Arthritis Rheum 52・12
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.;Okumura S et al.;Nakamichi Y et al.;Tsukiyama K et al.;Itoh S et al.;Yamamoto Y et al.;Udagawa N et al.;Okumura S et al.;Takahashi N et al.;Yamaki M;Kobayashi Y;Kobayashi Y;Yang S;Take I;Tsuboi H
通讯作者：
Tsuboi H

Arthritis Research, Methods and Protocols Volume 1 "Generation of osteoclasts in vitro, and assay of osteoclast activity"

关节炎研究、方法和方案第 1 卷“体外破骨细胞的生成以及破骨细胞活性的测定”

DOI：
发表时间：
2006
期刊：
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.;Okumura S et al.;Nakamichi Y et al.;Tsukiyama K et al.;Itoh S et al.;Yamamoto Y et al.;Udagawa N et al.;Okumura S et al.;Takahashi N et al.;Yamaki M;Kobayashi Y;Kobayashi Y;Yang S;Take I;Tsuboi H;Takahashi N et al.
通讯作者：
Takahashi N et al.