title: Icariside II activates EGFR-Akt-Nrf2 signaling and protects osteoblasts from dexamethasone.
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.
authors.affiliation: Department of Orthopedics, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Endocrinology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.
authors.forename: Li
authors.initials: L
authors.lastname: Mao
authors.affiliation: Department of Orthopedics, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Ji
authors.affiliation: Clinical Laboratory, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.
authors.forename: Fengli
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Orthopedics, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.
authors.forename: Shouguo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Orthopedics, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xie
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D003907:Dexamethasone / Q000009:adverse effects*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002867:Chromones; D005419:Flavonoids; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D009025:Morpholines; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D010767:Phosphorylcholine; C060988:baohuoside I; C105905:perifosine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D003907:Dexamethasone; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt
keywords: EGFR-Akt; Nrf2 signaling; dexamethasone; icariside II; oxidative stress