Sodium butyrate activates ERK to regulate differentiation of mesenchymal stem cells.
Histone deacetylase inhibitors such as sodium butyrate are known to regulate the differentiation of a variety of cells. Mesenchymal stem cells (MSCs) differentiate into osteoblasts and adipocytes under transcriptional control of Runx2 and PPARgamma2, respectively. How these two transcription factors are regulated by sodium butyrate in order to specify the alternate cell fates remains a pivotal question. Sodium butyrate stimulated osteogenic differentiation and increased expression of Runx2 and genes regulated by Runx2 when cells were induced to undergo osteogenic differentiation. Sodium butyrate suppressed the adipogenic differentiation and decreased the expression of PPARgamma2 and LPL when MSCs were treated under conditions that promote adipogenic differentiation. Sodium butyrate also decreased the ratio of RANKL/OPG gene expression by MSCs. Analysis of MSCs induced in the presence of sodium butyrate revealed an immediate increase in ERK phosphorylation by sodium butyrate. The MEK-specific inhibitor, PD98059 but not p38- or JNK-specific inhibitor and the transfection with dominant negative ERK expressing plasmids blocked the sodium butyrate-induced regulation of MSC differentiation and increase in the RANKL/OPG ratio. Our results suggest that sodium butyrate modulates MSC differentiation and the RANKL/OPG ratio via activating ERK, and could be applied for in vivo bone growth using MSCs.
Chen
Tain-Hsiung
TH
Orthopaedics and Traumatology, Veterans General Hospital, Taipei, Taiwan. thchen@vghtpe.gov.tw
Chen
Wei-Ming
WM
Hsu
Ke-Hsun
KH
Kuo
Cheng-Deng
CD
Hung
Shih-Chieh
SC
D050156:Adipogenesis / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D010012:Osteogenesis / Q000187:drug effects; D053244:Osteoprotegerin / Q000235:genetics; D053245:RANK Ligand / Q000235:genetics; D012964:Sodium / Q000494:pharmacology*
D002087:Butyrates; D053244:Osteoprotegerin; D053245:RANK Ligand; D012964:Sodium; D048049:Extracellular Signal-Regulated MAP Kinases