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

Munoz, MA; Fletcher, EK; Skinner, OP; Jurczyluk, J; Kristianto, E; Hodson, MP; Sun, S; Ebetino, FH; Croucher, DR; Hansbro, PM; Center, JR; Rogers, MJ

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

Munoz, MA Fletcher, EK Skinner, OP Jurczyluk, J Kristianto, E Hodson, MP Sun, S Ebetino, FH Croucher, DR Hansbro, PM Center, JR Rogers, MJ

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Publisher:: eLife Sciences Publications Ltd
Publication Type:: Journal Article
Citation:: eLife, 2021, 10, pp. 1-15
Issue Date:: 2021-12-30

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Field	Value	Language
dc.contributor.author	Munoz, MA
dc.contributor.author	Fletcher, EK
dc.contributor.author	Skinner, OP
dc.contributor.author	Jurczyluk, J
dc.contributor.author	Kristianto, E
dc.contributor.author	Hodson, MP
dc.contributor.author	Sun, S
dc.contributor.author	Ebetino, FH
dc.contributor.author	Croucher, DR
dc.contributor.author	Hansbro, PM
dc.contributor.author	Center, JR
dc.contributor.author	Rogers, MJ
dc.date.accessioned	2022-01-28T01:59:45Z
dc.date.available	2021-12-19
dc.date.available	2022-01-28T01:59:45Z
dc.date.issued	2021-12-30
dc.identifier.citation	eLife, 2021, 10, pp. 1-15
dc.identifier.issn	2050-084X
dc.identifier.issn	2050-084X
dc.identifier.uri	http://hdl.handle.net/10453/153723
dc.description.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.
dc.format	Electronic
dc.language	eng
dc.publisher	eLife Sciences Publications Ltd
dc.relation	http://purl.org/au-research/grants/nhmrc/1175134
dc.relation.ispartof	eLife
dc.relation.isbasedon	10.7554/eLife.72430
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0601 Biochemistry and Cell Biology
dc.subject.mesh	Animals
dc.subject.mesh	Bone Density Conservation Agents
dc.subject.mesh	Chemokines
dc.subject.mesh	Cytokines
dc.subject.mesh	Female
dc.subject.mesh	Lipopolysaccharides
dc.subject.mesh	Lung
dc.subject.mesh	Macrophages, Alveolar
dc.subject.mesh	Macrophages, Peritoneal
dc.subject.mesh	Mevalonic Acid
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Protein Prenylation
dc.subject.mesh	Zoledronic Acid
dc.subject.mesh	Animals
dc.subject.mesh	Bone Density Conservation Agents
dc.subject.mesh	Chemokines
dc.subject.mesh	Cytokines
dc.subject.mesh	Female
dc.subject.mesh	Lipopolysaccharides
dc.subject.mesh	Lung
dc.subject.mesh	Macrophages, Alveolar
dc.subject.mesh	Macrophages, Peritoneal
dc.subject.mesh	Mevalonic Acid
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Protein Prenylation
dc.subject.mesh	Zoledronic Acid
dc.title	Bisphosphonate drugs have actions in the lung and inhibit the mevalonate pathway in alveolar macrophages.
dc.type	Journal Article
utslib.citation.volume	10
utslib.location.activity	England
utslib.for	0601 Biochemistry and Cell Biology
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access	*
pubs.consider-herdc	false
dc.date.updated	2022-01-28T01:59:41Z
pubs.publication-status	Published online
pubs.volume	10

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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http://hdl.handle.net/10453/153723