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.
Highlights
Nitrogen-c ontaining bisphosphonates (N-B Ps) are a class of bone-seeking drugs used worldwide as the frontline treatment for disorders of excessive bone resorption such as post-menopausal osteoporosis and cancer-associated bone disease (Russell, 2011)
Like most other fluorescently labelled N-BPs (Roelofs et al, 2010), AF647-Z OL did not inhibit protein prenylation compared to the parent N-BP (ZOL) when tested in cultures of bone marrow-d erived macrophages (BMDM; Figure 1a), but can be used to track drug uptake by cells in vivo (Junankar et al, 2015)
Animals were injected with a single intravenous (i.v.) dose of AF647-Z OL, and cells collected by bronchoalveolar lavage (BAL) were analysed by flow cytometry
Summary
Nitrogen-c ontaining bisphosphonates (N-B Ps) are a class of bone-seeking drugs used worldwide as the frontline treatment for disorders of excessive bone resorption such as post-menopausal osteoporosis and cancer-associated bone disease (Russell, 2011). By virtue of their avidity for calcium ions, N-B Ps bind rapidly to the skeleton, where they are internalised by bone-d egrading osteoclasts. Respiratory diseases constitute the most common cause of death, and therapies that boost the immune response to common lung infections are urgently needed Bacterial infections such as Streptococcus pneumoniae, Haemophilus influenzae, Chlamydia pneumoniae, and Staphylococcus aureus are the main cause of community-a cquired pneumonia. We debunk the long-h eld view that N-B P drugs act only in the skeleton in healthy mice and show that even a single dose of N-B P in mice is sufficient to affect tissue-resident macrophages, including lung alveolar macrophages (AMΦ), boosting their response to bacterial endotoxin
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