Bisphosphonate drugs have actions in the lung and inhibit the mevalonate pathway in alveolar macrophages

Bisphosphonates drugs target the skeleton and are used globally for the treatment of common bone disorders. Nitrogen-containing bisphosphonates act by inhibiting the mevalonate pathway in bone-resorbing osteoclasts but, surprisingly, also appear to reduce the risk of death from pneumonia. We overtur...

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Bibliographic Details
Published in:eLife Vol. 10
Main Authors: Munoz, Marcia A, Fletcher, Emma K, Skinner, Oliver P, Jurczyluk, Julie, Kristianto, Esther, Hodson, Mark P, Sun, Shuting, Ebetino, Frank H, Croucher, David R, Hansbro, Philip M, Center, Jacqueline R, Rogers, Michael J
Format: Journal Article
Language:English
Published: England eLife Sciences Publications Ltd 30.12.2021
eLife Sciences Publications, Ltd
Subjects:
alveolar macrophage
Animals
Bacterial infections
bisphosphonate
Bisphosphonates
Bone Density Conservation Agents - administration & dosage
Bone Density Conservation Agents - pharmacology
Bone diseases
Bone loss
Bone marrow
Bronchus
Chemokines
Chemokines - metabolism
Chromatography
Cytokines
Cytokines - metabolism
Drug dosages
Female
Flow cytometry
Fractures
Immune response
Immunosuppressive agents
inflammasome
Lavage
Lipopolysaccharides - toxicity
Lung - drug effects
Lung - metabolism
Macrophages
Macrophages, Alveolar - drug effects
Macrophages, Peritoneal - drug effects
Mass spectrometry
Medicine
Mevalonate pathway
Mevalonic acid
Mevalonic Acid - metabolism
Mice
Mice, Inbred C57BL
Mortality
Osteoclasts
Osteoporosis
Pneumonia
prenylation
Protein Prenylation - drug effects
Proteins
Scientific imaging
Short Report
Skeleton
Streptococcus infections
Zoledronic acid
Zoledronic Acid - administration & dosage
Zoledronic Acid - pharmacology
mouse
alveolar macrophage
pneumonia
inflammasome
bisphosphonate
prenylation
medicine
osteoporosis
ISSN:2050-084X, 2050-084X
Online Access:Get full text
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Summary:Bisphosphonates drugs target the skeleton and are used globally for the treatment of common bone disorders. Nitrogen-containing bisphosphonates act by inhibiting the mevalonate pathway in bone-resorbing osteoclasts but, surprisingly, also appear to reduce the risk of death from pneumonia. We overturn the long-held belief that these drugs act only in the skeleton and show that a fluorescently labelled bisphosphonate is internalised by alveolar macrophages and large peritoneal macrophages in vivo. Furthermore, a single dose of a nitrogen-containing bisphosphonate (zoledronic acid) in mice was sufficient to inhibit the mevalonate pathway in tissue-resident macrophages, causing the build-up of a mevalonate metabolite and preventing protein prenylation. Importantly, one dose of bisphosphonate enhanced the immune response to bacterial endotoxin in the lung and increased the level of cytokines and chemokines in bronchoalveolar fluid. These studies suggest that bisphosphonates, as well as preventing bone loss, may boost immune responses to infection in the lung and provide a mechanistic basis to fully examine the potential of bisphosphonates to help combat respiratory infections that cause pneumonia.
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ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.72430