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The working mechanism of bone resorption inhibitory protein induced by osteoclasts

破骨细胞诱导骨吸收抑制蛋白的作用机制

基本信息

批准号：
15390648
负责人：
NOGUCHI Toshihide
金额：
$ 8.06万
依托单位：
Aichi-Gakuin 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 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390648/
关键词：
OIP-1 IFN-γ Periodontitis Bone resorption Osteoclast IL-1β

项目摘要

Periodontitis is a chronic inflammatory disease caused by infections with Gram-negative bacteria and characterized by alveolar bone resorption. It is very critical to inhibit bone resorption for treatment and prevention of periodontitis. The osteoclast (OCL) is the primary bone resorbing cell and there are many reports about intracellular signaling pathway related with OCL differentiation. It is possible to control bone resorption if we could manage this signaling pathway. Our collaborator identified OCL inhibitory peptide-1 (OIP-1/hSca) as a novel inhibitor of OCL formation and bone resorption that is produced by OCLs. OIP-1 is a unique protein from OCLs to be able to inhibit OCL differentiation by itself. Our main object of this study is to seek the possibility for clinical application of OIP-1 in periodontitis by expoloring the mechanism of this OCL inhibition. We used cycle-dependent reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, which demonstrated that interfer … More on-γ (IFN-γ) strongly enhanced OIP-1/hSca mRNA expression in mouse bone marrow cells and osteoblasts. Similarly, interleukin (IL)-12 also enhanced OIP-1 mRNA expression. To determine the participation of OIP-1 in IFN-γ inhibition of OCL formation, we tested the capacity of a neutralizing antibody specific to OIP-1 c-peptide to inhibit IFN-γ's effects on OCL-like cell differentiation of mouse macrophages, RAW 264.7 cells. Anti-OIP-1 c-peptide specific antibody partially neutralized IFN-γ inhibition of OCL differentiation. Furthermore, OIP-1 inhibited phospho-c-Jun (p-c-Jun) kinase activity in RAW 264.7 cells. However, OIP-1/hSca did not affect NF-κB activation hi these cells. Western blot analysis further demonstrated that OIP-1 significantly decreased TNF receptor associated factor 2 (TRAF-2) expression in RAW 264.7 cells. However, OIP-1 had no effect on TRAF-6 expression in these cells. These data show that IFN-γ enhances OIP-1/hSca expression in mouse bone marrow cells and osteoblasts, and that OIP-1 inhibits OCL formation through suppression of TRAF-2 and p-c-Jun kinase activity. These findings suggest the possibility by OIP-1 to inhibit inflammatory bone resorption in periodontitis Less

牙周炎是由革兰氏阴性菌感染引起的以牙槽骨吸收为特征的慢性炎症性疾病。抑制骨吸收对牙周炎的防治至关重要。破骨细胞（OCL）是主要的骨吸收细胞，有关OCL分化相关的细胞内信号通路的研究已有很多报道。如果我们能够控制这个信号通路，就有可能控制骨吸收。我们的合作者确定OCL抑制肽-1（OIP-1/hSca）作为OCL形成和骨吸收的新型抑制剂，由OCL产生。OIP-1是来自OCL的独特蛋白质，能够自身抑制OCL分化。本研究的主要目的是探讨OIP-1抑制OCL的机制，为OIP-1在牙周炎中的临床应用提供可能。我们使用了依赖于细胞周期的逆转录-聚合酶链反应（RT-PCR）分析，结果表明干扰素 ...更多信息 IFN-γ能显著增强小鼠骨髓细胞和成骨细胞OIP-1/hSca mRNA的表达。同样，白细胞介素（IL）-12也增强OIP-1 mRNA的表达。为了确定OIP-1在OCL形成的IFN-γ抑制中的参与，我们测试了对OIP-1 c-肽特异性的中和抗体抑制IFN-γ对小鼠巨噬细胞RAW 264.7细胞的OCL样细胞分化的作用的能力。抗OIP-1 c肽特异性抗体部分中和IFN-γ对OCL分化的抑制。此外，OIP-1抑制RAW 264.7细胞中的磷酸-c-Jun（p-c-Jun）激酶活性。但OIP-1/hSca对NF-κB的活化无明显影响。Western印迹分析进一步证明OIP-1显著降低RAW 264.7细胞中TNF受体相关因子2（TRAF-2）的表达。然而，OIP-1对这些细胞中TRAF-6的表达没有影响。这些数据表明，IFN-γ增强小鼠骨髓细胞和成骨细胞中的OIP-1/hSca表达，并且OIP-1通过抑制TRAF-2和p-c-Jun激酶活性来抑制OCL形成。这些发现表明OIP-1抑制牙周炎炎性骨吸收的可能性。