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

doi:10.3389/fphar.2022.1002550

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

Front Pharmacol. 2022 Oct 14:13:1002550. doi: 10.3389/fphar.2022.1002550. eCollection 2022.

Authors

Prajakta Kalkar¹, Gal Cohen^{1

2}, Tal Tamari^{2

3}, Sagie Schif-Zuck¹, Hadar Zigdon-Giladi^{2

3}, Amiram Ariel¹

Affiliations

¹ Departments of Biology and Human Biology, University of Haifa, Haifa, Israel.
² Laboratory for Bone Repair, Rambam Health Care Campus, Haifa, Israel.
³ The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

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.

Keywords: IFN-β; dexamethasone; macrophages; multiple myeloma; osteoclast differentiation; resolution of inflammation; zoledronic acid.