Zfp521 is a target gene and key effector of parathyroid hormone-related peptide signaling in growth plate chondrocytes

Diego Correa, Eric Hesse, Dutmanee Seriwatanachai, Riku Kiviranta, Hiroaki Saito, Kei Yamana, Lynn Neff, Azeddine Atfi, Lucie Coillard, Despina Sitara, Yukiko Maeda, Soren Warming, Nancy A. Jenkins, Neal G. Copeland, William C. Horne, Beate Lanske, Roland Baron

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

In the growth plate, the interplay between parathyroid hormone-related peptide (PTHrP) and Indian hedgehog (Ihh) signaling tightly regulates chondrocyte proliferation and differentiation during longitudinal bone growth. We found that PTHrP increases the expression of Zfp521, a zinc finger transcriptional coregulator, in prehypertrophic chondrocytes. Mice with chondrocyte-targeted deletion of Zfp521 resembled PTHrP-/- and chondrocyte-specific PTHR1-/- mice, with decreased chondrocyte proliferation, early hypertrophic transition, and reduced growth plate thickness. Deleting Zfp521 increased expression of Runx2 and Runx2 target genes, and decreased Cyclin D1 and Bcl-2 expression while increasing Caspase-3 activation and apoptosis. Zfp521 associated with Runx2 in chondrocytes, antagonizing its activity via an HDAC4-dependent mechanism. PTHrP failed to upregulate Cyclin D1 and to antagonize Runx2, Ihh, and collagen X expression when Zfp521 was absent. Thus, Zfp521 is an important PTHrP target gene that regulates growth plate chondrocyte proliferation and differentiation.

Original languageEnglish (US)
Pages (from-to)533-546
Number of pages14
JournalDevelopmental Cell
Volume19
Issue number4
DOIs
StatePublished - Oct 19 2010
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Correa, D., Hesse, E., Seriwatanachai, D., Kiviranta, R., Saito, H., Yamana, K., Neff, L., Atfi, A., Coillard, L., Sitara, D., Maeda, Y., Warming, S., Jenkins, N. A., Copeland, N. G., Horne, W. C., Lanske, B., & Baron, R. (2010). Zfp521 is a target gene and key effector of parathyroid hormone-related peptide signaling in growth plate chondrocytes. Developmental Cell, 19(4), 533-546. https://doi.org/10.1016/j.devcel.2010.09.008