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

Dev Cell. 2010 Oct 19;19(4):533-46. doi: 10.1016/j.devcel.2010.09.008.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Biomarkers / metabolism
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Chondrocytes / drug effects
  • Chondrocytes / enzymology
  • Chondrocytes / metabolism*
  • Chondrocytes / pathology
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Gene Deletion
  • Gene Expression Regulation, Developmental / drug effects
  • Growth Plate / metabolism
  • Growth Plate / pathology*
  • Histone Deacetylases / metabolism
  • Hypertrophy
  • Mice
  • Mice, Knockout
  • Osteogenesis / drug effects
  • Parathyroid Hormone-Related Protein / metabolism*
  • Parathyroid Hormone-Related Protein / pharmacology
  • Repressor Proteins / metabolism
  • Signal Transduction* / drug effects
  • Transcription Factors / metabolism*


  • Biomarkers
  • Core Binding Factor Alpha 1 Subunit
  • Evi3 protein, mouse
  • Parathyroid Hormone-Related Protein
  • Repressor Proteins
  • Runx2 protein, mouse
  • Transcription Factors
  • Hdac5 protein, mouse
  • Histone Deacetylases