title: Coordinated transcriptional regulation of bone homeostasis by Ebf1 and Zfp521 in both mesenchymal and hematopoietic lineages.
abstract: Bone homeostasis is maintained by the coupled actions of hematopoietic bone-resorbing osteoclasts (OCs) and mesenchymal bone-forming osteoblasts (OBs). Here we identify early B cell factor 1 (Ebf1) and the transcriptional coregulator Zfp521 as components of the machinery that regulates bone homeostasis through coordinated effects in both lineages. Deletion of Zfp521 in OBs led to impaired bone formation and increased OB-dependent osteoclastogenesis (OC-genesis), and deletion in hematopoietic cells revealed a strong cell-autonomous role for Zfp521 in OC progenitors. In adult mice, the effects of Zfp521 were largely caused by repression of Ebf1, and the bone phenotype of Zfp521(+/-) mice was rescued in Zfp521(+/-):Ebf1(+/-) mice. Zfp521 interacted with Ebf1 and repressed its transcriptional activity. Accordingly, deletion of Zfp521 led to increased Ebf1 activity in OBs and OCs. In vivo, Ebf1 overexpression in OBs resulted in suppressed bone formation, similar to the phenotype seen after OB-targeted deletion of Zfp521. Conversely, Ebf1 deletion led to cell-autonomous defects in both OB-dependent and cell-intrinsic OC-genesis, a phenotype opposite to that of the Zfp521 knockout. Thus, we have identified the interplay between Zfp521 and Ebf1 as a novel rheostat for bone homeostasis.
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Harvard University, Boston, MA 02115, USA.
authors.forename: Riku
authors.initials: R
authors.lastname: Kiviranta
authors.forename: Kei
authors.initials: K
authors.lastname: Yamana
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Saito
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Ho
authors.forename: Julius
authors.initials: J
authors.lastname: Laine
authors.forename: Kati
authors.initials: K
authors.lastname: Tarkkonen
authors.forename: Vappu
authors.initials: V
authors.lastname: Nieminen-Pihala
authors.forename: Eric
authors.initials: E
authors.lastname: Hesse
authors.forename: Diego
authors.initials: D
authors.lastname: Correa
authors.forename: Jorma
authors.initials: J
authors.lastname: Määttä
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.forename: Evan D
authors.initials: ED
authors.lastname: Rosen
authors.forename: William C
authors.initials: WC
authors.lastname: Horne
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: Soren
authors.initials: S
authors.lastname: Warming
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
mesh_terms: D000818:Animals; D001851:Bone Diseases, Metabolic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D019070:Cell Lineage / Q000235:genetics*; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005854:Germ Cells / Q000378:metabolism; D057895:Haploinsufficiency; D006413:Hematopoietic System / Q000473:pathology*; D006706:Homeostasis / Q000235:genetics*; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis; D010641:Phenotype; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C489921:Ebf1 protein, mouse; C472572:Evi3 protein, mouse; C493716:Runx2 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors