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

Prajakta Kalkar, Gal Cohen, Tal Tamari, Sagie Schif-Zuck, Hadar Zigdon-Giladi, Amiram Ariel

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number1002550
JournalFrontiers in Pharmacology
Volume13
DOIs
StatePublished - 14 Oct 2022

Bibliographical note

Funding Information:
The study was supported by grants from the Israel Science Foundation (Grant No. 678/13), the Rosetrees Trust (Grant No. M535), and the Wolfson Family Charitable Trust.

Publisher Copyright:
Copyright © 2022 Kalkar, Cohen, Tamari, Schif-Zuck, Zigdon-Giladi and Ariel.

Keywords

  • dexamethasone
  • IFN-β
  • macrophages
  • multiple myeloma
  • osteoclast differentiation
  • resolution of inflammation
  • zoledronic acid

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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