Coordinated transcriptional regulation of bone homeostasis by Ebf1 and Zfp521 in both mesenchymal and hematopoietic lineages.
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Coordinated transcriptional regulation of bone homeostasis by Ebf1 and Zfp521 in both mesenchymal and hematopoietic lineages. / Kiviranta, Riku; Yamana, Kei; Saito, Hiroaki; Ho, Daniel K; Laine, Julius; Tarkkonen, Kati; Nieminen-Pihala, Vappu; Hesse, Eric; Correa, Diego; Määttä, Jorma; Tessarollo, Lino; Rosen, Evan D; Horne, William C; Jenkins, Nancy A; Copeland, Neal G; Warming, Soren; Baron, Roland.
in: J EXP MED, Jahrgang 210, Nr. 5, 5, 2013, S. 969-985.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Coordinated transcriptional regulation of bone homeostasis by Ebf1 and Zfp521 in both mesenchymal and hematopoietic lineages.
AU - Kiviranta, Riku
AU - Yamana, Kei
AU - Saito, Hiroaki
AU - Ho, Daniel K
AU - Laine, Julius
AU - Tarkkonen, Kati
AU - Nieminen-Pihala, Vappu
AU - Hesse, Eric
AU - Correa, Diego
AU - Määttä, Jorma
AU - Tessarollo, Lino
AU - Rosen, Evan D
AU - Horne, William C
AU - Jenkins, Nancy A
AU - Copeland, Neal G
AU - Warming, Soren
AU - Baron, Roland
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - Animals
KW - Mice
KW - Gene Deletion
KW - Phenotype
KW - Transcription, Genetic
KW - Core Binding Factor Alpha 1 Subunit/metabolism
KW - Transcription Factors/metabolism
KW - Gene Expression Regulation
KW - Haploinsufficiency
KW - Osteogenesis
KW - Up-Regulation/genetics
KW - Osteoblasts/metabolism/pathology
KW - Trans-Activators/metabolism
KW - Cell Lineage/genetics
KW - Osteoclasts/metabolism/pathology
KW - Bone Diseases, Metabolic/metabolism/pathology/physiopathology
KW - Bone Resorption/metabolism/pathology/physiopathology
KW - Bone and Bones/metabolism/pathology/physiopathology
KW - Germ Cells/metabolism
KW - Hematopoietic System/pathology
KW - Homeostasis/genetics
KW - Mesoderm/pathology
KW - Animals
KW - Mice
KW - Gene Deletion
KW - Phenotype
KW - Transcription, Genetic
KW - Core Binding Factor Alpha 1 Subunit/metabolism
KW - Transcription Factors/metabolism
KW - Gene Expression Regulation
KW - Haploinsufficiency
KW - Osteogenesis
KW - Up-Regulation/genetics
KW - Osteoblasts/metabolism/pathology
KW - Trans-Activators/metabolism
KW - Cell Lineage/genetics
KW - Osteoclasts/metabolism/pathology
KW - Bone Diseases, Metabolic/metabolism/pathology/physiopathology
KW - Bone Resorption/metabolism/pathology/physiopathology
KW - Bone and Bones/metabolism/pathology/physiopathology
KW - Germ Cells/metabolism
KW - Hematopoietic System/pathology
KW - Homeostasis/genetics
KW - Mesoderm/pathology
M3 - SCORING: Journal article
VL - 210
SP - 969
EP - 985
JO - J EXP MED
JF - J EXP MED
SN - 0022-1007
IS - 5
M1 - 5
ER -