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

氨基二膦酸盐（aminoBPs）有望成为治疗骨吸收增强疾病的有效药物。然而，在临床应用中，炎症副作用被反复报道。在我们对组胺形成酶（组氨酸脱羧酶，HDC）的研究过程中，我们发现这些药物会引起小鼠的异常炎症反应，如HDC诱导时间延长，粒细胞数量增加，实验性关节炎（类风湿关节炎的一种模型）加重等。本项目的目的是阐明氨基obps的炎症作用机制，我们证明了以下几点：1。AHBuBP是一种典型的氨基obp，它能增加脂多糖诱导的HDC活性的升高和IL-1的产生，但抑制脂多糖诱导的TNF的产生。结果表明，在lps作用下，给予ahbbp的小鼠中增加的巨噬细胞负责增加IL-1的产生。Cl2MBP是一种非氨基obp，可以抑制氨基obp诱导的炎症反应，提高HDC活性，增加IL-1的产生。然而，Cl2MBP不抑制LPS诱导的HDC活性升高。基于这些结果，我们提出了bp特异性受体可能存在的想法。（《英国药理学杂志》，已出版）牙周炎致病菌中普雷沃氏菌的AHBuBP和LPS均能提高小鼠下颌骨的HDC活性。此外，AHBuBP显著增强lps诱导的下颌骨HDC活性升高。(在提交)4。东京大学的Iwakura博士提供了利用基因靶向技术生产的il -i缺陷小鼠。我们发现，在il -1缺失的小鼠中，由氨基obps引起的炎症反应、HDC活性升高和il -1产生增加都被消除，这表明il -1介导了氨基obps的炎症作用。在本研究中，我们阐明了il - 1介导氨基obps的炎症作用。我们的进一步发现，氨基obp的炎症作用几乎完全被Cl2MBP（一种非氨基obp）所阻止，这意味着氨基obp和非氨基obp共同给药可能是一种有用的临床策略，可以预防氨基obp的炎症副作用。在我们下一步的研究中，阐明这一发现的生物学意义和机制是非常重要和有趣的。少

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