Zfp521 antagonizes Runx2, delays osteoblast differentiation in vitro, and promotes bone formation in vivo.
Zfp521, a 30 C2H2 Kruppel-like zinc finger protein, is expressed at high levels at the periphery of early mesenchymal condensations prefiguring skeletal elements and in all developing bones in the perichondrium and periosteum, in osteoblast precursors and osteocytes, and in chondroblast precursors and growth plate prehypertrophic chondrocytes. Zfp521 expression in cultured mesenchymal cells is decreased by BMP-2 and increased by PTHrP, which promote and antagonize osteoblast differentiation, respectively. In vitro, Zfp521 overexpression reduces the expression of several downstream osteoblast marker genes and antagonizes osteoblast differentiation. Zfp521 binds Runx2 and represses its transcriptional activity, and Runx2 dose-dependently rescues Zfp521's inhibition of osteoblast differentiation. In contrast, osteocalcin promoter-targeted overexpression of Zfp521 in osteoblasts in vivo results in increased bone formation and bone mass. We propose that Zfp521 regulates the rate of osteoblast differentiation and bone formation during development and in the mature skeleton, in part by antagonizing Runx2.
Wu
Meilin
M
Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Hesse
Eric
E
Morvan
Frederic
F
Zhang
Jian-Ping
JP
Correa
Diego
D
Rowe
Glenn C
GC
Kiviranta
Riku
R
Neff
Lynn
L
Philbrick
William M
WM
Horne
William C
WC
Baron
Roland
R
D000818:Animals; D015152:Blotting, Northern; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology*; D011519:Proto-Oncogenes / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C499305:Mecom protein, mouse; D014157:Transcription Factors