title: OSU53 Rescues Human OB-6 Osteoblastic Cells from Dexamethasone through Activating AMPK Signaling.
abstract: Excessive dexamethasone (Dex) application causes osteoblast cell death, which could lead to osteoporosis or osteonecrosis. AMP-activated protein kinase (AMPK) activation is shown to protect osteoblasts/osteoblastic cells from Dex. In this report, we tested the potential effect of OSU53, a novel AMPK activator, in Dex-treated osteoblastic cells. We show that OSU53 activated AMPK signaling in human OB-6 osteoblastic cells. Further, Dex-induced osteoblastic OB-6 cell death and apoptosis were largely attenuated with pre-treatment with OSU53. OSU53 was more efficient than other known AMPK activators (A-769662 and Compound 13) in protecting OB-6 cells against Dex. AMPK activation is required for OSU53-induced actions in OB-6 cells. AMPKα shRNA knockdown or dominant-negative mutation (dn-AMPKα T172A) almost completely blocked OSU53-induced AMPK activation and OB-6 cell protection against Dex. Further studies showed that OSU53 increased NADPH (nicotinamide adenine dinucleotide phosphate) activity and alleviated Dex-induced oxidative stress in OB-6 cells. Such effects by OSU53 were again almost abolished with AMPKα shRNA or dn-AMPKα in OB-6 cells. Together, these results demonstrate that OSU53 protects osteoblastic cells from Dex possibly via activating AMPK-dependent signaling.
authors.affiliation: The Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Xu
authors.affiliation: The Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: The Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Zhu
authors.affiliation: The Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Fan
authors.affiliation: The Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China.
authors.forename: Shengyu
authors.initials: S
authors.lastname: Cui
authors.affiliation: The Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China.
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: The Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: The Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: The Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, 226001, China.
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Cui
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D006801:Humans; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D000263:Adenylate Kinase; D003907:Dexamethasone; D020536:Enzyme Activators; D013449:Sulfonamides; D045162:Thiazolidinediones; C549054:N-(4-(3-(1-methyl-cyclohexylmethyl)-2,4-dioxothiazolidin-5-ylidenemethyl)phenyl)-4-nitro-3-trifluoromethylbenzenesulfonamide; D000096926:Benzenesulfonamides