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

// Weidong Liu 1, * , Li Mao 2, * , Feng Ji 1 , Fengli Chen 3 , Shouguo Wang 1 , Yue Xie 1 1 Department of Orthopedics, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, China 2 Department of Endocrinology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, China 3 Clinical Laboratory, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, China * Co-first authors Correspondence to: Feng Ji, email: huaiaifengjidr@163.com Keywords: icariside II, dexamethasone, EGFR-Akt, Nrf2 signaling, oxidative stress Received: November 07, 2016      Accepted: November 21, 2016      Published: December 01, 2016 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.