title: A new regulator of osteoclastogenesis: estrogen response element-binding protein in bone.
abstract: The heterogeneous nuclear ribonucleoprotein (hnRNP)-like estrogen response element-binding protein (ERE-BP) competes with estrogen receptor α (ERα) for occupancy of estrogen response elements (EREs). Here we report that ERE-BP potently stimulates osteoclastogenesis. ERE-BP mRNA and protein were found to be expressed ubiquitously in bone. Overexpression of ERE-BP in cultured osteoblasts stimulated expression of the receptor activator of NF-κB ligand (RANKL) and decreased osteoprotegerin (OPG). The effect of ERE-BP on RANKL was shown to be transcriptional in transient transfection assay and competed with via the ER. Constitutive expression of ERE-BP increased the sensitivity of cells toward 1,25-dihydroxyvitamin D(3) stimulation of RANKL expression. In contrast, knockdown of ERE-BP in stromal ST-2 cells decreased basal RANKL promoter activity. Cocultures of ERE-BP lentivirus-transduced ST-2 cells with spleen monocytes induced formation of multinucleated osteoclasts (OCs) characterized by tartrate-resistant acid phosphatase, calcitonin receptors, and functional calcium resorption from bone slices. Although ERα competed with ERE-BP for an ERE in a dose-dependent manner, ERE-BP was an independent and potent regulator of RANKL and osteoclastogenesis. In preosteoclastic RAW cells, overexpression of ERE-BP increased RANK, upregulated NF-κB signaling, and enhanced differentiation toward a mature OC phenotype independent of RANKL. These results identify ERE-BP as a potent modulator of osteoclastogenesis. We hypothesize that ERE-BP may play a critical role in the regulation of bone homeostasis as a modulator of estrogen sensitivity as well as by direct action on the transcription of critical osteoclastogenic genes.
authors.affiliation: Veterans Administration Medical Center and Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Linda C
authors.initials: LC
authors.lastname: Gilbert
authors.forename: X
authors.initials: X
authors.lastname: Lu
authors.forename: Zhaofan
authors.initials: Z
authors.lastname: Liu
authors.forename: Shaojin
authors.initials: S
authors.lastname: You
authors.forename: M Neale
authors.initials: MN
authors.lastname: Weitzmann
authors.forename: Mark S
authors.initials: MS
authors.lastname: Nanes
authors.forename: John
authors.initials: J
authors.lastname: Adams
mesh_terms: D000818:Animals; D001483:Base Sequence; D001842:Bone and Bones / Q000378:metabolism*; D002454:Cell Differentiation; D018920:Coculture Techniques; D017931:DNA Primers; D004967:Estrogens / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology*; D011401:Promoter Regions, Genetic; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D004967:Estrogens; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse