Studies of limitin for prevention of bone resorption in bacterial periodontitis

限制素预防细菌性牙周炎骨吸收的研究

• 批准号: 16591836
• 负责人: SATO Takuya
• 金额: $ 2.24万
• 依托单位: Meikai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591836/
• 关键词: limitin; osteoclasts; periodontitis; bone resorption; B細胞

Periodontitis is a bacterial disease and causes tooth loss due to alveolar bone resorption. Immunological reaction due to periodontitis, that is necessary for prevention of systemic infection of the bacteria, results in excessive osteoclastogenesis. Therefore, it is important for treatment of periodontitis to inhibit osteoclastogenesis without diminishing immunological reactions. Limitin is a type-I interferon (IFN) like cytokine and known to stimulate immune responses. Since the other type-I IFN, IFN-beta, inhibits osteoclastogenesis, I hypothesized that limitin also could prevent osteoclastogenesis with stimulatory effects on immune systems. In this project, I studied the effects of limitin on osteoclastogenesis and the mechanism of the effects. I found that limitin strongly inhibits osteoclastogenesis in vitro cultures. On the other hand, limitin stimulated productions of inflammatory cytokines, such as TNF-alpha and RANKL, by CD3-activated T cells. When explored the mechanism of the inhibitory effect of limitin on osteoclastogenesis, I found that limitin decreases c-fos content in osteoclast precursors and stimulates PKR mRNA expression, which is known to be up-regulated in virul infection and to inhibit protein synthesis. Limitin also inhibited transcription of NFATc1 that is a master gene of osteoclastogenesis and is activated by a combination of transcription factors including c-fos. When PKR mRNA was decreased by siRNA technique, limitin did not diminished c-fos content and osteoclastogenesis. These data suggest that limitin inhibits osteoclastogenesis via PKR-dependent inhibition of c-fos synthesis. Limitin is a potential therapeutic factor for prevention of bone loss in periodontal diseases.

牙周炎是一种细菌性疾病，由于牙槽骨吸收而导致牙齿脱落。牙周炎引起的免疫反应是预防细菌全身感染所必需的，导致破骨细胞过度生成。因此，在不降低免疫反应的情况下抑制破骨细胞的生成对于牙周炎的治疗是重要的。Limitin是一种I型干扰素（IFN）样细胞因子，已知可刺激免疫应答。由于另一种I型干扰素IFN-β抑制破骨细胞生成，我假设限制素也可以通过刺激免疫系统来阻止破骨细胞生成。本课题主要研究限制素对破骨细胞生成的影响及其作用机制。我发现limitin在体外培养中强烈抑制破骨细胞的生成。另一方面，限制素刺激CD 3激活的T细胞产生炎性细胞因子，如TNF-α和RANKL。当探索限制素对破骨细胞生成的抑制作用的机制时，我发现限制素降低破骨细胞前体中的c-fos含量并刺激PKR mRNA表达，已知PKR mRNA在病毒感染中上调并抑制蛋白质合成。Limitin还抑制NFATc 1的转录，NFATc 1是破骨细胞生成的主基因，并由包括c-fos在内的转录因子的组合激活。当PKR mRNA通过siRNA技术降低时，limitin不降低c-fos含量和破骨细胞生成。这些数据表明，限制素抑制破骨细胞通过PKR依赖性抑制c-fos合成。Limitin是一种潜在的预防牙周病骨丢失的治疗因子。