title: Selective regulation of osteoblastic OPG and RANKL by dehydroepiandrosterone through activation of the estrogen receptor β-mediated MAPK signaling pathway.
abstract: The aim of the work was to investigate the differential regulation by dehydroepiandrosterone (DHEA) of the osteoblastic production via the estrogen receptor beta (ER β)-mediated signaling pathway. Having developed hMG63-ER β cells and hMG63-shER β cells, we analyzed the regulation by DHEA of human osteoblastic viability, the receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG), and the differential expression of ER β, ER α, or p-ERK1/2 (extracellular signal-regulated kinase) in hMG63, hMG63-shER β, and hMG63-ER β cells pretreated with or without U0126, flutamide, and ICI 182780, followed by DHEA culture. When the level of ER β was high, DHEA (10 - 7  mol/l) could effectively amplify the proliferation and inhibit the etoposide-induced apoptosis of hMG63 cells (p<0.01 and p<0.05, respectively), which was blocked by U0126. When the expression of ER β was silenced, DHEA could not significantly improve the viability of hMG63. In the presence of ER β, DHEA activated the pERK1/2-MAPK signaling pathway but not p38 and JNK. Besides, the regulation of p-ERK1/2 upon DHEA treatment was mainly modulated by ER β instead of androgen receptor and ER α. The secretion of OPG was declined following the silence of ER β (p<0.05). RANKL and ER α, however, were unaffected by culture with or without DHEA and U0126, regardless of the ER β level. DHEA seems to act selectively on osteoblasts via the dominant ER β receptor, which mediates amplified cell viability through the MAPK signaling pathway involving pERK1/2 and upregulates the production of OPG rather than RANKL.
authors.affiliation: International Peace Maternal and Child Health Hospital, Shanghai Jiaotong University, Shanghai, P. R. China.
authors.forename: Y-D
authors.initials: YD
authors.lastname: Wang
authors.forename: M-F
authors.initials: MF
authors.lastname: Tao
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: W-W
authors.initials: WW
authors.lastname: Cheng
authors.forename: X-P
authors.initials: XP
authors.lastname: Wan
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D053244:Osteoprotegerin / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D003687:Dehydroepiandrosterone; D048049:Extracellular Signal-Regulated MAP Kinases