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IFN-β mediates the anti-osteoclastic effect of bisphosphonates and dexamethasone

Zoledronic acid (Zol) is a potent bisphosphonate that inhibits the differentiation of monocytes into osteoclasts. It is often used in combination with dexamethasone (Dex), a glucocorticoid that promotes the resolution of inflammation, to treat malignant diseases, such as multiple myeloma. This treat...

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Autores principales: Kalkar, Prajakta, Cohen, Gal, Tamari, Tal, Schif-Zuck, Sagie, Zigdon-Giladi, Hadar, Ariel, Amiram
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9648992/
https://www.ncbi.nlm.nih.gov/pubmed/36386129
http://dx.doi.org/10.3389/fphar.2022.1002550
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author Kalkar, Prajakta
Cohen, Gal
Tamari, Tal
Schif-Zuck, Sagie
Zigdon-Giladi, Hadar
Ariel, Amiram
author_facet Kalkar, Prajakta
Cohen, Gal
Tamari, Tal
Schif-Zuck, Sagie
Zigdon-Giladi, Hadar
Ariel, Amiram
author_sort Kalkar, Prajakta
collection PubMed
description Zoledronic acid (Zol) is a potent bisphosphonate that inhibits the differentiation of monocytes into osteoclasts. It is often used in combination with dexamethasone (Dex), a glucocorticoid that promotes the resolution of inflammation, to treat malignant diseases, such as multiple myeloma. This treatment can result in bone pathologies, namely medication related osteonecrosis of the jaw, with a poor understanding of the molecular mechanism on monocyte differentiation. IFN-β is a pro-resolving cytokine well-known as an osteoclast differentiation inhibitor. Here, we explored whether Zol and/or Dex regulate macrophage osteoclastic differentiation via IFN-β. RAW 264.7 and peritoneal macrophages were treated with Zol and/or Dex for 4–24 h, and IFN-β secretion was examined by ELISA, while the IFN stimulated gene (ISG) 15 expression was evaluated by Western blotting. RANKL-induced osteoclastogenesis of RAW 264.7 cells was determined by TRAP staining following treatment with Zol+Dex or IFN-β and anti-IFN-β antibodies. We found only the combination of Zol and Dex increased IFN-β secretion by RAW 264.7 macrophages at 4 h and, correspondingly, ISG15 expression in these cells at 24 h. Moreover, Zol+Dex blocked osteoclast differentiation to a similar extent as recombinant IFN-β. Neutralizing anti-IFN-β antibodies reversed the effect of Zol+Dex on ISG15 expression and partially recovered osteoclastic differentiation induced by each drug alone or in combination. Finally, we found Zol+Dex also induced IFN-β expression in peritoneal resolution phase macrophages, suggesting these drugs might be used to enhance the resolution of acute inflammation. Altogether, our findings suggest Zol+Dex block the differentiation of osteoclasts through the expression of IFN-β. Revealing the molecular pathway behind this regulation may lead to the development of IFN-β-based therapy to inhibit osteoclastogenesis in multiple myeloma patients.
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spelling pubmed-96489922022-11-15 IFN-β mediates the anti-osteoclastic effect of bisphosphonates and dexamethasone Kalkar, Prajakta Cohen, Gal Tamari, Tal Schif-Zuck, Sagie Zigdon-Giladi, Hadar Ariel, Amiram Front Pharmacol Pharmacology Zoledronic acid (Zol) is a potent bisphosphonate that inhibits the differentiation of monocytes into osteoclasts. It is often used in combination with dexamethasone (Dex), a glucocorticoid that promotes the resolution of inflammation, to treat malignant diseases, such as multiple myeloma. This treatment can result in bone pathologies, namely medication related osteonecrosis of the jaw, with a poor understanding of the molecular mechanism on monocyte differentiation. IFN-β is a pro-resolving cytokine well-known as an osteoclast differentiation inhibitor. Here, we explored whether Zol and/or Dex regulate macrophage osteoclastic differentiation via IFN-β. RAW 264.7 and peritoneal macrophages were treated with Zol and/or Dex for 4–24 h, and IFN-β secretion was examined by ELISA, while the IFN stimulated gene (ISG) 15 expression was evaluated by Western blotting. RANKL-induced osteoclastogenesis of RAW 264.7 cells was determined by TRAP staining following treatment with Zol+Dex or IFN-β and anti-IFN-β antibodies. We found only the combination of Zol and Dex increased IFN-β secretion by RAW 264.7 macrophages at 4 h and, correspondingly, ISG15 expression in these cells at 24 h. Moreover, Zol+Dex blocked osteoclast differentiation to a similar extent as recombinant IFN-β. Neutralizing anti-IFN-β antibodies reversed the effect of Zol+Dex on ISG15 expression and partially recovered osteoclastic differentiation induced by each drug alone or in combination. Finally, we found Zol+Dex also induced IFN-β expression in peritoneal resolution phase macrophages, suggesting these drugs might be used to enhance the resolution of acute inflammation. Altogether, our findings suggest Zol+Dex block the differentiation of osteoclasts through the expression of IFN-β. Revealing the molecular pathway behind this regulation may lead to the development of IFN-β-based therapy to inhibit osteoclastogenesis in multiple myeloma patients. Frontiers Media S.A. 2022-10-14 /pmc/articles/PMC9648992/ /pubmed/36386129 http://dx.doi.org/10.3389/fphar.2022.1002550 Text en Copyright © 2022 Kalkar, Cohen, Tamari, Schif-Zuck, Zigdon-Giladi and Ariel. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Kalkar, Prajakta
Cohen, Gal
Tamari, Tal
Schif-Zuck, Sagie
Zigdon-Giladi, Hadar
Ariel, Amiram
IFN-β mediates the anti-osteoclastic effect of bisphosphonates and dexamethasone
title IFN-β mediates the anti-osteoclastic effect of bisphosphonates and dexamethasone
title_full IFN-β mediates the anti-osteoclastic effect of bisphosphonates and dexamethasone
title_fullStr IFN-β mediates the anti-osteoclastic effect of bisphosphonates and dexamethasone
title_full_unstemmed IFN-β mediates the anti-osteoclastic effect of bisphosphonates and dexamethasone
title_short IFN-β mediates the anti-osteoclastic effect of bisphosphonates and dexamethasone
title_sort ifn-β mediates the anti-osteoclastic effect of bisphosphonates and dexamethasone
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9648992/
https://www.ncbi.nlm.nih.gov/pubmed/36386129
http://dx.doi.org/10.3389/fphar.2022.1002550
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