Histone Deacetylase 3 Deletion in Mesenchymal Progenitor Cells Hinders Long Bone Development

Marina Feigenson, Lomeli Carpio Shull, Earnest L. Taylor, Emily T. Camilleri, Scott M. Riester, Andre J van Wijnen, Elizabeth Bradley, Jennifer J Westendorf

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Long bone formation is a complex process that requires precise transcriptional control of gene expression programs in mesenchymal progenitor cells. Histone deacetylases (Hdacs) coordinate chromatin structure and gene expression by enzymatically removing acetyl groups from histones and other proteins. Hdac inhibitors are used clinically to manage mood disorders, cancers, and other conditions but are teratogenic to the developing skeleton and increase fracture risk in adults. In this study, the functions of Hdac3, one of the enzymes blocked by current Hdac inhibitor therapies, in skeletal mesenchymal progenitor cells were determined. Homozygous deletion of Hdac3 in Prrx1-expressing cells prevented limb lengthening, altered pathways associated with endochondral and intramembranous bone development, caused perinatal lethality, and slowed chondrocyte and osteoblast differentiation in vitro. Transcriptomic analysis revealed that Hdac3 regulates vastly different pathways in mesenchymal cells expressing the Prxx1-Cre driver than those expressing the Col2-CreERT driver. Notably, Fgf21 was elevated in Hdac3-CKOPrrx1 limbs as well as in chondrogenic cells exposed to Hdac3 inhibitors. Elevated expression of Mmp3 and Mmp10 transcripts was also observed. In conclusion, Hdac3 regulates distinct pathways in mesenchymal cell populations and is required for mesenchymal progenitor cell differentiation and long bone development.

Original languageEnglish (US)
Pages (from-to)2453-2465
Number of pages13
JournalJournal of Bone and Mineral Research
Volume32
Issue number12
DOIs
StatePublished - Dec 1 2017

    Fingerprint

Keywords

  • CHONDROGENESIS
  • FGF21
  • HDAC3
  • LIMB DEVELOPMENT
  • MMP10
  • MMP3
  • RGFP966
  • VORINOSTAT

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this