Bisphosphonate drugs have actions in the lung and inhibit the mevalonate pathway in alveolar macrophages
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Curated by eLife
Evaluation Summary:
The manuscript by Munoz et al describes the effect of the bisphosphonate zoledronic acid on tissue-resident macrophages. For this, the investigators used both a fluorescent bisphosphonate derivative and an unmodified zoledronic acid, in combination with macrophage populations isolated from different tissues. Based on the pattern of cytokines released by macrophages in the presence of zoledronic acid, the authors conclude that administration of bisphosphonates could, in addition to preventing bone loss, boost immune responses and lessen the consequences of respiratory infections.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)
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- Pharmacology and Toxicology (eLife)
Abstract
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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Author Response:
We thank the reviewers for highlighting the importance and potential clinical significance of our findings. The concentration of bisphosphonate drug in tissues outside the skeleton, such as lung, are unknown and we recognise that further studies are needed to determine whether the effects of a bisphosphonate that we describe in mice also occur in humans with standard clinical doses of these drugs. Nonetheless, our findings add further weight to the view that bisphosphonate therapy has benefits beyond just preventing bone loss and could be considered as prophylactic agents to reduce the risk of pneumonia in individuals with osteopenia or osteoporosis, who are already eligible for treatment under standard clinical guidelines.
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Evaluation Summary:
The manuscript by Munoz et al describes the effect of the bisphosphonate zoledronic acid on tissue-resident macrophages. For this, the investigators used both a fluorescent bisphosphonate derivative and an unmodified zoledronic acid, in combination with macrophage populations isolated from different tissues. Based on the pattern of cytokines released by macrophages in the presence of zoledronic acid, the authors conclude that administration of bisphosphonates could, in addition to preventing bone loss, boost immune responses and lessen the consequences of respiratory infections.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share …
Evaluation Summary:
The manuscript by Munoz et al describes the effect of the bisphosphonate zoledronic acid on tissue-resident macrophages. For this, the investigators used both a fluorescent bisphosphonate derivative and an unmodified zoledronic acid, in combination with macrophage populations isolated from different tissues. Based on the pattern of cytokines released by macrophages in the presence of zoledronic acid, the authors conclude that administration of bisphosphonates could, in addition to preventing bone loss, boost immune responses and lessen the consequences of respiratory infections.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)
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Reviewer #1 (Public Review):
The paper reports in a mouse study that the potent N-containing bisphosphonate, zoledronate, can directly enter alveolar macrophages and peritoneal macrophages and exercise biological activity, inhibiting the Farnesyl diphosphate synthase enzyme. The paper is technically of a high standard.
The present work shows for the first time that an N-BP can directly internalize into non - bone cells following IV injection. It shows further that the internalized ZOL can prevent protein prenylation, with increased IL-1 and other cytokines and chemokines that constitute the inflammosome. The authors propose that their immunopharmacology studies present an explanation for N- bisphosphonate improvement of outcome of patients with pneumonia.
These pharmacological experiments provide an exciting prospect for clinical …
Reviewer #1 (Public Review):
The paper reports in a mouse study that the potent N-containing bisphosphonate, zoledronate, can directly enter alveolar macrophages and peritoneal macrophages and exercise biological activity, inhibiting the Farnesyl diphosphate synthase enzyme. The paper is technically of a high standard.
The present work shows for the first time that an N-BP can directly internalize into non - bone cells following IV injection. It shows further that the internalized ZOL can prevent protein prenylation, with increased IL-1 and other cytokines and chemokines that constitute the inflammosome. The authors propose that their immunopharmacology studies present an explanation for N- bisphosphonate improvement of outcome of patients with pneumonia.
These pharmacological experiments provide an exciting prospect for clinical application, and this will be especially so if the effect of N-BPs can be shown to take place with drug concentrations that might be achievable clinically.
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Reviewer #2 (Public Review):
The manuscript by Munoz et al. is aimed at identifying possible mechanisms by which the clinical outcome of pneumonia can be improved by previous or concurrent treatment with aminobisphosphonates (NBP). The study was motivated by epidemiological and clinical data linking the treatment with zoledronic acid (ZOL) for hip fractures or other skeletal-related events with a reduced risk of mortality from pneumonia. The Authors conclude that zoledronic acid (ZOL), commonly used to prevent bone loss in cancer and osteoporosis, targets the mevalonate pathway in alveolar macrophages of C57BL/6J mice and boosts protective inflammatory and immune responses after bacterial endotoxin (LPS) challenge.
The results are interesting and based on experiments well designed and well performed. ZOL is a drug commonly used in the …
Reviewer #2 (Public Review):
The manuscript by Munoz et al. is aimed at identifying possible mechanisms by which the clinical outcome of pneumonia can be improved by previous or concurrent treatment with aminobisphosphonates (NBP). The study was motivated by epidemiological and clinical data linking the treatment with zoledronic acid (ZOL) for hip fractures or other skeletal-related events with a reduced risk of mortality from pneumonia. The Authors conclude that zoledronic acid (ZOL), commonly used to prevent bone loss in cancer and osteoporosis, targets the mevalonate pathway in alveolar macrophages of C57BL/6J mice and boosts protective inflammatory and immune responses after bacterial endotoxin (LPS) challenge.
The results are interesting and based on experiments well designed and well performed. ZOL is a drug commonly used in the clinics with a very safe record track. It is always exciting when an inexpensive and safe drug sounds promising for repositioning.
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Reviewer #3 (Public Review):
This is a well-written manuscript that clearly shows the ability of macrophages outside bone to incorporate bisphosphonates intracellularly and respond to zoledronic acid administration by increasing the production of proinflammatory cytokines and chemokines. The data appears solid, and the conclusions are supported by the data. The experimental design mimics the outcomes of individuals already treated with bisphosphonates when they encounter an infection, mimicked here by administration of the bacterial endotoxin, and the authors seem to imply it could also be used as a preventive measure in elderly patients. Related to the latter point, and if the reviewer's understanding is correct, authors could include a more direct statement describing the potential use as a prophylactic agent.
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