Zfp521 controls bone mass by HDAC3-dependent attenuation of Runx2 activity.
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Zfp521 controls bone mass by HDAC3-dependent attenuation of Runx2 activity. / Hesse, Eric; Saito, Hiroaki; Kiviranta, Riku; Correa, Diego; Yamana, Kei; Neff, Lynn; Toben, Daniel; Duda, Georg; Atfi, Azeddine; Geoffroy, Valérie; Horne, William C; Baron, Roland.
in: J CELL BIOL, Jahrgang 191, Nr. 7, 7, 2010, S. 1271-1283.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Zfp521 controls bone mass by HDAC3-dependent attenuation of Runx2 activity.
AU - Hesse, Eric
AU - Saito, Hiroaki
AU - Kiviranta, Riku
AU - Correa, Diego
AU - Yamana, Kei
AU - Neff, Lynn
AU - Toben, Daniel
AU - Duda, Georg
AU - Atfi, Azeddine
AU - Geoffroy, Valérie
AU - Horne, William C
AU - Baron, Roland
PY - 2010
Y1 - 2010
N2 - Runx2 is indispensable for osteoblast lineage commitment and early differentiation but also blocks osteoblast maturation, thereby causing bone loss in Runx2 transgenic mice. Zinc finger protein 521 (Zfp521) antagonizes Runx2 in vivo. Eliminating one Zfp521 allele mitigates the cleidocranial dysplasia-like phenotype of newborn Runx2(+/-) mice, whereas overexpressing Zfp521 exacerbates it. Overexpressing Zfp521 also reverses the severe osteopenia of adult Runx2 transgenic mice. Zfp521 binds to both Runx2 and histone deacetylase 3 (HDAC3), promotes their association, and antagonizes Runx2 transcriptional activity in an HDAC3-dependent manner. Mutating the Zfp521 zinc finger domains 6 and 26 reduces the binding of Zfp521 to Runx2 and inhibition of Runx2 activity. These data provide evidence that Zfp521 antagonizes Runx2 in vivo and thereby regulates two stages of osteoblast development, early during mesenchymal cell lineage commitment and later during osteoblast maturation. Thus, the balance and molecular interplay between Zfp521 and Runx2 contribute to the control of osteoblast differentiation, skeletal development, and bone homeostasis.
AB - Runx2 is indispensable for osteoblast lineage commitment and early differentiation but also blocks osteoblast maturation, thereby causing bone loss in Runx2 transgenic mice. Zinc finger protein 521 (Zfp521) antagonizes Runx2 in vivo. Eliminating one Zfp521 allele mitigates the cleidocranial dysplasia-like phenotype of newborn Runx2(+/-) mice, whereas overexpressing Zfp521 exacerbates it. Overexpressing Zfp521 also reverses the severe osteopenia of adult Runx2 transgenic mice. Zfp521 binds to both Runx2 and histone deacetylase 3 (HDAC3), promotes their association, and antagonizes Runx2 transcriptional activity in an HDAC3-dependent manner. Mutating the Zfp521 zinc finger domains 6 and 26 reduces the binding of Zfp521 to Runx2 and inhibition of Runx2 activity. These data provide evidence that Zfp521 antagonizes Runx2 in vivo and thereby regulates two stages of osteoblast development, early during mesenchymal cell lineage commitment and later during osteoblast maturation. Thus, the balance and molecular interplay between Zfp521 and Runx2 contribute to the control of osteoblast differentiation, skeletal development, and bone homeostasis.
KW - Animals
KW - Mice
KW - Rats
KW - Heterozygote
KW - Mice, Transgenic
KW - Animals, Newborn
KW - Cell Count
KW - Mice, Inbred Strains
KW - Alkaline Phosphatase/metabolism
KW - Bone Development/physiology
KW - Bone Diseases, Metabolic/genetics/metabolism
KW - Bone Remodeling/physiology
KW - Bone and Bones/abnormalities/embryology/metabolism/pathology
KW - Calcification, Physiologic/genetics
KW - Cell Differentiation/genetics
KW - Core Binding Factor Alpha 1 Subunit/antagonists & inhibitors/genetics/metabolism
KW - DNA-Binding Proteins/genetics/metabolism
KW - Extracellular Matrix Proteins/genetics
KW - Fractures, Spontaneous/genetics
KW - Gene Expression/genetics
KW - Histone Deacetylase Inhibitors/pharmacology
KW - Histone Deacetylases/genetics/metabolism
KW - Mesenchymal Stem Cells/cytology
KW - Osteoblasts/cytology/metabolism
KW - Osteocalcin/genetics
KW - Osteogenesis/physiology
KW - Osteopontin/genetics
KW - Osteoprotegerin/genetics
KW - Protein Binding/physiology
KW - Protein Interaction Domains and Motifs/physiology
KW - RANK Ligand/genetics
KW - Response Elements/physiology
KW - Transcription Factors/genetics
KW - Transcription, Genetic/drug effects/genetics
KW - Zinc Fingers/physiology
KW - Animals
KW - Mice
KW - Rats
KW - Heterozygote
KW - Mice, Transgenic
KW - Animals, Newborn
KW - Cell Count
KW - Mice, Inbred Strains
KW - Alkaline Phosphatase/metabolism
KW - Bone Development/physiology
KW - Bone Diseases, Metabolic/genetics/metabolism
KW - Bone Remodeling/physiology
KW - Bone and Bones/abnormalities/embryology/metabolism/pathology
KW - Calcification, Physiologic/genetics
KW - Cell Differentiation/genetics
KW - Core Binding Factor Alpha 1 Subunit/antagonists & inhibitors/genetics/metabolism
KW - DNA-Binding Proteins/genetics/metabolism
KW - Extracellular Matrix Proteins/genetics
KW - Fractures, Spontaneous/genetics
KW - Gene Expression/genetics
KW - Histone Deacetylase Inhibitors/pharmacology
KW - Histone Deacetylases/genetics/metabolism
KW - Mesenchymal Stem Cells/cytology
KW - Osteoblasts/cytology/metabolism
KW - Osteocalcin/genetics
KW - Osteogenesis/physiology
KW - Osteopontin/genetics
KW - Osteoprotegerin/genetics
KW - Protein Binding/physiology
KW - Protein Interaction Domains and Motifs/physiology
KW - RANK Ligand/genetics
KW - Response Elements/physiology
KW - Transcription Factors/genetics
KW - Transcription, Genetic/drug effects/genetics
KW - Zinc Fingers/physiology
M3 - SCORING: Journal article
VL - 191
SP - 1271
EP - 1283
JO - J CELL BIOL
JF - J CELL BIOL
SN - 0021-9525
IS - 7
M1 - 7
ER -