SC79 rescues osteoblasts from dexamethasone though activating Akt-Nrf2 signaling.
Dexamethasone (Dex) causes osteoblast cell injuries. In the present research, we tested the potential effect of SC79, a novel and specific Akt activator, against Dex in osteoblasts. In primary murine osteoblasts and osteoblastic MC3T3-E1 cells, pretreatment with SC79 significantly attenuated Dex-induced cell death. Further, Dex-induced mitochondrial permeability transition pore (mPTP) opening, cytochrome C release and apoptosis activation were dramatically alleviated with SC79 pretreatment in above cells. At the molecular level, SC79 activated Akt, which was indispensable for subsequent osteoblast protection against Dex. Akt inhibitors (LY294002, perifosine and MK-2206) blocked SC79-induced Akt activation and abolished its anti-Dex actions in osteoblasts. Further, SC79 activated Akt downstream Nrf2 (NF-E2-related factor 2) signaling and attenuated Dex-induced oxidative stress in osteoblasts. Nrf2 shRNA knockdown or S40T mutation almost reversed SC79-mediated anti-oxidant and cytoprotective activities in osteoblasts. Together, these results suggest that SC79 activates Akt-Nrf2 signaling to protect osteoblasts from Dex.
The Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Song-Tao
ST
Li
Institute of Neuroscience, Soochow University, Suzhou, China.
Nan-Nan
NN
Chen
Department of Surgery, The Third Hospital Affiliated to Soochow University, Changzhou City, Jiangsu, 213003, China.
Yin-Biao
YB
Qiao
Changshu Entry-Exit Inspection and Quarantine Bureau, Changshu, China.
Wei-Li
WL
Zhu
The Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China; The Department of Orthopedics, Taizhou Municipal Hospital, Taizhou City, Zhejiang, China. Electronic address: ray-tzmh@hotmail.com.
Jian-Wei
JW
Ruan
The Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China. Electronic address: zhouxiaozhongorth@163.com.
Xiao-Zhong
XZ
Zhou
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001578:Benzopyrans / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D051379:Mice; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
C000614067:AKT activator SC79; D000085:Acetates; D000893:Anti-Inflammatory Agents; D001578:Benzopyrans; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D003907:Dexamethasone; D045304:Cytochromes c; D051057:Proto-Oncogene Proteins c-akt
Akt; Dexamethasone (Dex); Nrf2; Oxidant stress; SC79