Zfp521 controls bone mass by HDAC3-dependent attenuation of Runx2 activity

Eric Hesse, Hiroaki Saito, Riku Kiviranta, Diego Correa, Kei Yamana, Lynn Neff, Daniel Toben, Georg Duda, Azeddine Atfi, Valérie Geoffroy, William C. Horne, Roland Baron

Research output: Contribution to journalArticle

67 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1271-1283
Number of pages13
JournalJournal of Cell Biology
Volume191
Issue number7
DOIs
StatePublished - Dec 27 2010

ASJC Scopus subject areas

  • Cell Biology

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    Hesse, E., Saito, H., Kiviranta, R., Correa, D., Yamana, K., Neff, L., Toben, D., Duda, G., Atfi, A., Geoffroy, V., Horne, W. C., & Baron, R. (2010). Zfp521 controls bone mass by HDAC3-dependent attenuation of Runx2 activity. Journal of Cell Biology, 191(7), 1271-1283. https://doi.org/10.1083/jcb.201009107