title: Effects of Na/K-ATPase and its ligands on bone marrow stromal cell differentiation.
abstract: Endogenous ligands of Na/K-ATPase have been demonstrated to increase in kidney dysfunction and heart failure. It is also reported that Na/K-ATPase signaling function effects stem cell differentiation. This study evaluated whether Na/K-ATPase activation through its ligands and associated signaling functions affect bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) differentiation capacity. BMSCs were isolated from male Sprague-Dawley rats and cultured in minimal essential medium alpha (MEM-α) supplemented with 15% Fetal Bovine serum (FBS). The results showed that marinobufagenin (MBG), a specific Na/K-ATPase ligand, potentiated rosiglitazone-induced adipogenesis in these BMSCs. Meanwhile, it attenuated BMSC osteogenesis. Mechanistically, MBG increased CCAAT/enhancer binding protein alpha (C/EBPα) protein expression through activation of an extracellular regulated kinase (ERK) signaling pathway, which leads to enhanced rosiglitazone-induced adipogenesis. Inhibition of ERK activation by U0126 blocks the effect of MBG on C/EBPα expression and on rosiglitazone-induced adipogenesis. Reciprocally, MBG reduced runt-related transcription factor 2 (RunX2) expression, which resulted in the inhibition of osteogenesis induced by β-glycerophosphate/ascorbic acid. MBG also potentiated rosiglitazone-induced adipogenesis in 3T3-L1 cells and in mouse BMSCs. These results suggest that Na/K-ATPase and its signaling functions are involved in the regulation of BMSCs differentiation.
authors.affiliation: Department of Medicine, University of Toledo, Toledo, OH, USA.
authors.forename: Moustafa
authors.initials: M
authors.lastname: Sayed
authors.affiliation: Department of Medicine, University of Toledo, Toledo, OH, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Drummond
authors.affiliation: Department of Medicine, University of Toledo, Toledo, OH, USA.
authors.forename: Kaleigh L
authors.initials: KL
authors.lastname: Evans
authors.affiliation: Department of Medicine, University of Toledo, Toledo, OH, USA.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Haller
authors.affiliation: Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Toledo, Toledo, OH, USA.
authors.forename: Zijian
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Department of Medicine, University of Toledo, Toledo, OH, USA. Electronic address: Jiang.Tian@utoledo.edu.
authors.forename: Jiang
authors.initials: J
authors.lastname: Tian
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002018:Bufanolides / Q000494:pharmacology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D002018:Bufanolides; D022762:CCAAT-Enhancer-Binding Proteins; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C093896:marinobufagenin; D000254:Sodium-Potassium-Exchanging ATPase