Inflammatory and anti-inflammatory actions of bisphosphonates, inhibitors of bone resorption

双膦酸盐（骨吸收抑制剂）的炎症和抗炎作用

• 批准号: 09470409
• 负责人: ENDO Yasuo
• 金额: $ 0.9万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470409/
• 关键词: inhibitors of bone resorption; bisphosphonates; inflammation; cytokines; IL-1; TNF; histamine; LPS; 骨粗鬆症

Aminobisphosphonates (aminoBPs) are expected to be effective drugs for diseases with enhanced bone resorption. However, inflammatory side effects in their clinical applications are repeatedly reported. In the course of our studies on the histamine-forming enzyme (histidine decarboxylase, HDC), we found that these drugs induce abnormal inflammatory reactions in mice such as prolonged induction of HDC, increased number of granulocytic cells, exacerbation of experimental arthritis (a model of rheumatoid arthritis), etc. The aim of this project is to clarify the mechanism of the inflammatory actions of aminoBPs and we demonstrated the following :1. AHBuBP, a typical aminoBP, augments both of the elevation of HDC activity and the production of IL-1 induced by LPS, but this agent suppresses the production of TNF induced by LPS.It was clarified that macrophages increased in mice given AHBuBP are responsible for the augmentation of IL-1 production in response to LPS.2. Cl2MBP, a non-aminoBP, c … More an suppress inflammatory reactions, elevation of HDC activity and augmentation of IL-1 production induced by aminoBPs. However, Cl2MBP did not suppress the elevation of HDC activity induced by LPS.Based on these results, we presented the idea that specific receptors for BPs might be present. (British Journal of Pharmacology, in press)3. Both AHBuBP and LPS of Prevotella intermedia, a causative bacterium of periodontitis, elevate HDC activity in the mandible of mice. In addition, AHBuBP markedly augments the LPS-induced elevation of HDC activity in the mandible. (under submission)4. IL-i-deficient mice, which were produced by using gene-targeting techniques, were provided Dr. Iwakura of Tokyo University. We found that inflammatory reactions, elevation of HDC activity and augmentation of IL-i production induced by aminoBPs are all abolished in the IL-1-deficient mice, indicating that IL-i mediates the inflammatory actions of aminoBPs. (in preparation)In this study, we clarified that IL-i mediates the inflammatory actions of aminoBPs. Our additional finding that the inflammatory actions of aminoBPs are almost completely prevented by Cl2MBP, a non-aminoBP, means that co-administration of an aminoBP and a non-aminoBP may be a useful clinical strategy to prevent inflammatory side effects of aminoBPs. In the next step of our study, it is important and interesting to clarify the biological meaning and the mechanism of this finding. Less

氨基二膦酸盐（Aminobisphosphonates，aminobPs）有望成为治疗骨吸收增强疾病的有效药物。然而，其临床应用中的炎性副作用被反复报道。在我们研究组胺形成酶的过程中组氨酸脱羧酶（histidine decarboxylase，HDC）诱导小鼠出现异常炎症反应，如HDC诱导时间延长，粒细胞增多，实验性关节炎加重等（类风湿性关节炎模型）等。该项目的目的是阐明氨基BP的炎症作用机制，我们证明了以下内容：1.结论：1. AHBuBP是一种典型的氨基BP，能增强LPS诱导的HDC活性和IL-1的产生，但抑制LPS诱导的TNF的产生，提示AHBuBP诱导的小鼠巨噬细胞增多是LPS诱导的IL-1产生增加的原因. Cl 2 MBP，a非氨基BP，c ...更多信息 抑制由氨基BP诱导的炎症反应，提高HDC活性和增加IL-1的产生。然而，Cl_2MBP不能抑制LPS诱导的HDC活性的升高。基于这些结果，我们提出了可能存在BP的特异性受体的想法。（英国药理学杂志，出版中）3。牙周炎致病菌中间普雷沃氏菌的AHBuBP和LPS均能提高小鼠下颌骨中HDC的活性。此外，AHBuBP显著增强LPS诱导的下颌骨HDC活性升高。（提交中）4.东京大学的Iwakura博士提供了通过使用基因靶向技术产生的IL-1缺陷小鼠。我们发现，在IL-1缺陷小鼠中，氨基BP诱导的炎症反应、HDC活性升高和IL-1产生增加均被消除，表明IL-1介导了氨基BP的炎症作用。(in在这项研究中，我们阐明了IL-1介导氨基BP的炎症作用。我们的额外发现是，氨基BP的炎症作用几乎完全被Cl 2 MBP（一种非氨基BP）阻止，这意味着氨基BP和非氨基BP的共同施用可能是预防氨基BP的炎症副作用的有用临床策略。在我们研究的下一步中，阐明这一发现的生物学意义和机制是重要和有趣的。少

项目成果

菅原俊二 他: "Contrusting effects of an aminobisphosphenate on lipopolysaccharide-induced production of IL-1 and TNF in mice" British Journal of Pharmacology. 125. 735-740 (1998)

Shunji Sukawara 等人：“氨基双膦酸盐对脂多糖诱导的小鼠 IL-1 和 TNF 产生的影响”英国药理学杂志 125. 735-740 (1998)。

遠藤康男 他: "Inhibition of inflammatory actions of aminobisphosphonates by dichloro-methylene bisphosphonate,a non-aminobisphosphonate" British Journal of Pharmacology. (印刷中). (1999)

Yasuo Endo 等人：“二氯亚甲基二膦酸盐（一种非氨基二膦酸盐）对氨基二膦酸盐的炎症作用的抑制”《英国药理学杂志》（出版中）。

遠藤康男 他: "Inhibition of inflammatory actions of aminobisphosphonute by dichlorometlylene bisphosphonate, a non-ominobisphosphonute" Brifish Joumal of Pharmacology. (印刷中). (1999)

Yasuo Endo 等人：“二氯亚甲基双膦酸盐（一种非氨基双膦酸盐）对氨基二膦酸盐的炎症作用的抑制”Brifish Journal of Pharmacology（出版中）。

Yasuo Endo, Masahiko Shibazaki, Masanori Nakamura and Hiroshi Kosugi.: "Inhibition of inflammatory actions of aminobisphosphonates by dichloromethylene bisphosphonate, a non-aminobisphosphonate" British Journal of Pharmacology. (in press).

Yasuo Endo、Masahiko Shibazaki、Masanori Nakamura 和 Hiroshi Kosugi.：“二氯亚甲基二膦酸盐（一种非氨基二膦酸盐）对氨基二膦酸盐的炎症作用的抑制”英国药理学杂志。

菅原俊二 他: "Contrasting effects of an aminobisphosphonate on lipopolysaccharide-induced production of IL-1 and TNF in mice." Brifish Joumal of Pharmacology. 125. 735-740 (1998)

Shunji Sukawara 等人：“氨基二膦酸盐对脂多糖诱导的小鼠 IL-1 和 TNF 产生的影响对比。《Brifish 药理学杂志》125. 735-740 (1998)。