Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Language
Publication year range
1.
Bone ; 146: 115884, 2021 05.
Article in English | MEDLINE | ID: mdl-33582307

ABSTRACT

Early B cell factor 1 (Ebf1) is a transcription factor that regulates B cell, neuronal cell and adipocyte differentiation. We and others have shown that Ebf1 is expressed in osteoblasts and that global deletion of Ebf1 results in increased bone formation in vivo. However, as Ebf1 is expressed in multiple tissues and cell types, it has remained unclear, which of the phenotypic changes in bone are derived from bone cells. The aim of this study was to determine the cell-autonomous and differentiation stage-specific roles of Ebf1 in osteoblasts. In vitro, haploinsufficient Ebf1+/- calvarial cells showed impaired osteoblastic differentiation indicated by lower alkaline phosphatase (ALP) activity and reduced mRNA expression of osteoblastic genes, while overexpression of Ebf1 in wild type mouse calvarial cells led to enhanced osteoblast differentiation with increased expression of Osterix (Osx). We identified a putative Ebf1 binding site in the Osterix promoter by ChIP assay in MC3T3-E1 osteoblasts and showed that Ebf1 was able to activate Osx-luc reporter construct that included this Ebf1 binding site, suggesting that Ebf1 indeed regulates osteoblast differentiation by inducing Osterix expression. To reconcile our previous data and that of others with our novel findings, we hypothesized that Ebf1 could have a dual role in osteoblast differentiation promoting early but inhibiting late stages of differentiation and osteoblast function. To test this hypothesis in vivo, we generated conditional Ebf1 knockout mice, in which Ebf1 deletion was targeted to early or late osteoblasts by crossing Ebf1fl/fl mice with Osx- or Osteocalcin (hOC)-Cre mouse lines, respectively. Deletion of Ebf1 in early Ebf1Osx-/- osteoblasts resulted in significantly increased bone volume and trabecular number at 12 weeks by µCT analysis, while Ebf1hOC-/- mice did not have a bone phenotype. To conclude, our data demonstrate that Ebf1 promotes early osteoblast differentiation by regulating Osterix expression. However, Ebf1 inhibits bone accrual in the Osterix expressing osteoblasts in vivo but it is redundant in the maintenance of mature osteoblast function.


Subject(s)
Osteoblasts , Osteogenesis , Animals , B-Lymphocytes , Cell Differentiation , Mice , Osteocalcin , Sp7 Transcription Factor/genetics , Trans-Activators/genetics
2.
Bone ; 61: 33-8, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24389418

ABSTRACT

OBJECTIVES: Diabetes induces osteoporosis and during osteoporosis, vertebral bone marrow (VBM) adipose tissue amount increases. The association between this adiposity and bone marrow metabolism is unclear. Here, we compared VBM glucose metabolism and fat content in healthy and diabetic pigs, in vivo, using positron emission tomography (PET), in-phase and out-of-phase magnetic resonance imaging and magnetic resonance proton spectroscopy ((1)H MR spectroscopy). MATERIALS/METHODS: Eleven pigs (n=11) were used. The intervention group had five diabetic and the control group had six healthy pigs. To measure metabolism, PET-imaging with [(18)F]fluoro-deoxy-glucose ([(18)F]FDG) intravenous tracer was used. 1.5-T MRI with (1)H spectroscopy, in-phase and out-of-phase imaging and chemical TAG analysis of the VBM were performed. RESULTS: We found a significant inverse correlation between VBM glucose uptake (GU) and VBM fat content (R=-0.800, p<0.01) and TAG concentration assay (R=-0.846, p<0.05). There was a trend, although non-significant, of a linear correlation between VBM (1)H MR spectroscopy and TAG concentration (R=0.661) and (1)H MR spectroscopy and in-phase and out-of-phase MR imaging (R=0.635). CONCLUSIONS: VBM glucose metabolism coupled with VBM fat content may impact diabetic induced osteoporosis.


Subject(s)
Adipose Tissue/metabolism , Bone Marrow/metabolism , Diabetes Mellitus, Experimental/metabolism , Glucose/metabolism , Animals , Diabetes Mellitus, Experimental/complications , Disease Models, Animal , Fluorodeoxyglucose F18 , Magnetic Resonance Imaging , Male , Osteoporosis/etiology , Osteoporosis/metabolism , Positron-Emission Tomography , Radiopharmaceuticals , Spine/metabolism , Sus scrofa
3.
J Exp Med ; 210(5): 969-85, 2013 May 06.
Article in English | MEDLINE | ID: mdl-23569325

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.


Subject(s)
Bone and Bones/pathology , Cell Lineage/genetics , Gene Expression Regulation , Hematopoietic System/pathology , Homeostasis/genetics , Trans-Activators/metabolism , Transcription Factors/metabolism , Animals , Bone Diseases, Metabolic/metabolism , Bone Diseases, Metabolic/pathology , Bone Diseases, Metabolic/physiopathology , Bone Resorption/metabolism , Bone Resorption/pathology , Bone Resorption/physiopathology , Bone and Bones/metabolism , Bone and Bones/physiopathology , Core Binding Factor Alpha 1 Subunit/metabolism , Gene Deletion , Germ Cells/metabolism , Haploinsufficiency , Mesoderm/pathology , Mice , Osteoblasts/metabolism , Osteoblasts/pathology , Osteoclasts/metabolism , Osteoclasts/pathology , Osteogenesis , Phenotype , Transcription, Genetic , Up-Regulation/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...