Icariside II activates EGFR-Akt-Nrf2 signaling and protects osteoblasts from dexamethasone.

Weidong Liu,Yue Xie,Shouguo Wang,Feng Ji,Li Mao,Fengli Chen

doi:10.18632/oncotarget.13732

Abstract

The potential effect of icariside II on dexamethasone-induced osteoblast cell damages was evaluated here. In MC3T3-E1 osteoblastic cells and the primary murine osteoblasts, co-treatment with icariside II dramatically attenuated dexamethasone- induced cell death and apoptosis. Icariside II activated Akt signaling, which is required for its actions in osteoblasts. Akt inhibitors (LY294002, perifosine and MK-2206) almost abolished icariside II-induced osteoblast cytoprotection against dexamethasone. Further studies showed that icariside II activated Nrf2 signaling, downstream of Akt, to inhibit dexamethasone-induced reactive oxygen species (ROS) production in MC3T3-E1 cells and primary osteoblasts. On the other hand, Nrf2 shRNA knockdown inhibited icariside II-induced anti-dexamethasone cytoprotection in MC3T3-E1 cells. Finally, we showed that icariside II induced heparin-binding EGF (HB-EGF) production and EGFR trans-activation in MC3T3-E1 cells. EGFR inhibition, via anti-HB-EGF antibody, EGFR inhibitor AG1478 or EGFR shRNA knockdown, almost blocked icariside II-induced Akt-Nrf2 activation in MC3T3-E1 cells. Collectively, we conclude that icariside II activates EGFR-Akt-Nrf2 signaling and protects osteoblasts from dexamethasone. Icariside II might have translational value for the treatment of dexamethasone-associated osteoporosis/osteonecrosis.

Highlights

Dexamethasone (Dex) is a common anti-inflammatory medicine that is utilized by a huge number of patients [1]
We show that icariside II protects osteoblasts from Dex via activating epidermal growth factor receptor (EGFR)-Akt-NF-E2-related factor 2 (Nrf2) signaling
In order to study the potential effect of icariside II on Dex-induced cytotoxicity in osteoblasts, MC3T3-E1 osteoblastic cells were treated with Dex (1 μM) or www.impactjournals.com/oncotarget plus gradually increased concentration of icariside II (0.2–25 μM)

Summary

Introduction

Dexamethasone (Dex) is a common anti-inflammatory medicine that is utilized by a huge number of patients [1]. Excessive Dex application could cause secondary osteoporosis [2, 3] and/or osteonecrosis [4]. Studies have shown that about one third of patients with long-term Dex treatment could suffer bone damages [2]. Osteoblast cell apoptosis was often observed in bones of the Dex-using patients [2,3,4]. Exogenously-added Dex could induce direct damages to the cultured osteoblastic cells and osteoblasts [5,6,7,8,9,10]. The research focus of our group [5,6,7] is to explore the signaling mechanisms of Dex-induced osteoblast cell death, and to develop potential intervention strategies

Methods

Results

Conclusion