Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkaline Phosphatase / metabolism
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Animals
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Animals, Newborn
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Bone Development / physiology*
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Bone Diseases, Metabolic / genetics
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Bone Diseases, Metabolic / metabolism
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Bone Remodeling / physiology*
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Bone and Bones / abnormalities
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Bone and Bones / embryology
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Bone and Bones / metabolism
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Bone and Bones / pathology
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Calcification, Physiologic / genetics
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Cell Count
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Cell Differentiation / genetics
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Core Binding Factor Alpha 1 Subunit / antagonists & inhibitors
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Core Binding Factor Alpha 1 Subunit / genetics
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Core Binding Factor Alpha 1 Subunit / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Extracellular Matrix Proteins / genetics
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Fractures, Spontaneous / genetics
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Gene Expression / genetics
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Heterozygote
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Histone Deacetylase Inhibitors / pharmacology
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism*
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Mesenchymal Stem Cells / cytology
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Mice
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Mice, Inbred Strains
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Mice, Transgenic
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Osteoblasts / cytology
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Osteoblasts / metabolism
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Osteocalcin / genetics
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Osteogenesis / physiology*
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Osteopontin / genetics
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Osteoprotegerin / genetics
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Protein Binding / physiology
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Protein Interaction Domains and Motifs / physiology
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RANK Ligand / genetics
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Rats
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Response Elements / physiology
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Sp7 Transcription Factor
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Transcription Factors / genetics*
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Transcription, Genetic / drug effects
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Transcription, Genetic / genetics
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Zinc Fingers / physiology
Substances
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Core Binding Factor Alpha 1 Subunit
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DNA-Binding Proteins
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Dmp1 protein, mouse
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Evi3 protein, mouse
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Extracellular Matrix Proteins
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Histone Deacetylase Inhibitors
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Osteoprotegerin
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RANK Ligand
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Runx2 protein, mouse
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Sp7 Transcription Factor
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Sp7 protein, mouse
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Spp1 protein, mouse
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Tnfrsf11b protein, mouse
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Tnfsf11 protein, mouse
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Transcription Factors
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Osteocalcin
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Osteopontin
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Alkaline Phosphatase
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Histone Deacetylases
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histone deacetylase 3