title: Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells.
abstract: The identity of the paracrine mediator(s) of the antiresorptive action of estrogen on bone cells is controversial. Osteoprotegerin (OPG) was recently identified as a soluble member of the tumor necrosis factor (TNF) receptor (TNF-R) superfamily that is secreted by osteoblast lineage cells and acts by binding to and neutralizing its cognate ligand, OPG-L, a required factor for osteoclastogenesis. OPG prevents bone loss when administered to ovariectomized rats, induces osteoporosis when ablated in knock-out mice, and induces osteopetrosis when overexpressed in transgenic mice. In conditionally immortalized, human osteoblastic hFOB/ER-3 and hFOB/ER-9 cell lines containing physiological concentrations of approximately 800 and approximately 8,000 functional estrogen receptors (ER)/nucleus, respectively, we found that 17beta-estradiol dose- and time-dependently increased OPG mRNA and protein levels to maximal levels of 370% and 320%, respectively (P < 0.001); co-treatment with the "pure" antiestrogen ICI 182,780 abrogated these effects completely. 17beta-Estradiol also dose-dependently increased OPG mRNA and protein levels in normal human osteoblasts with approximately 400 ER/nucleus by 60% and 73%, respectively. Thus, estrogen enhancement of OPG secretion by osteoblastic cells may play a major role in the antiresorptive action of estrogen on bone.
authors.affiliation: Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Hofbauer
authors.forename: S
authors.initials: S
authors.lastname: Khosla
authors.forename: C R
authors.initials: CR
authors.lastname: Dunstan
authors.forename: D L
authors.initials: DL
authors.lastname: Lacey
authors.forename: T C
authors.initials: TC
authors.lastname: Spelsberg
authors.forename: B L
authors.initials: BL
authors.lastname: Riggs
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D000077267:Fulvestrant; D015870:Gene Expression / Q000187:drug effects*; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D053244:Osteoprotegerin; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D013997:Time Factors
chemical_list: D004965:Estrogen Antagonists; D006023:Glycoproteins; D053244:Osteoprotegerin; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; D000077267:Fulvestrant; D004958:Estradiol