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

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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