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Osteoblast-specific deletion of Hrpt2/Cdc73 results in high bone mass and increased bone turnover

Casey J Droscha1, Cassandra R Diegel1, Nicole J Ethen1

  • 1Program for Skeletal Disease and Tumor Microenvironment, Grand Rapids, MI, USA; Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA.

Bone
|April 7, 2017
PubMed

Insights

Loss of the Cdc73 gene (parafibromin) in mature bone cells disrupts gene expression, leading to increased bone mass and remodeling. This impacts transcriptional regulation and bone homeostasis.

Area of Science:

  • Genetics and Molecular Biology
  • Skeletal Biology and Bone Physiology
  • Epigenetics and Transcriptional Regulation

Background:

  • Inactivating mutations in the HRPT2/Cdc73 gene are linked to hyperparathyroidism and jaw ossifying fibromas (HPT-JT).
  • Parafibromin, the protein product of Cdc73, is a key component of the polymerase-associated factors (PAF) complex, regulating gene expression through epigenetic mechanisms.

Purpose of the Study:

  • To investigate the role of parafibromin in the mesenchymal lineage by conditionally deleting the Cdc73 gene.
  • To determine the consequences of parafibromin loss in mature osteoblasts and osteocytes on bone development and homeostasis.

Main Methods:

  • Conditional knockout mouse models using Dermo1-Cre and Ocn-Cre drivers to delete Cdc73 in specific cell populations.
  • Immunohistochemistry for cleaved caspase-3 to assess apoptosis.
  • RNA sequencing (RNA-seq) to analyze gene expression changes in osteoblasts.
  • Micro-computed tomography (micro-CT) and histological analysis of bone structure.

Main Results:

  • Homozygous deletion of Cdc73 in mesenchymal progenitors (Dermo1-Cre) led to embryonic lethality due to failed organ development and increased apoptosis.
  • Conditional deletion of Cdc73 in mature osteoblasts/osteocytes (Ocn-Cre) resulted in mice with normal lifespan but significantly increased cortical and trabecular bone.
  • OCN-Cre;Cdc73flox/flox bones showed enlarged cortical pores, active remodeling, osteocytes with high cytoplasmic RNA levels, and elevated apoptosis.
  • RNA-seq revealed derepression of osteoblast-specific genes, including collagen and bone matrix proteins, in OCN-Cre;Cdc73flox/flox osteoblasts.

Conclusions:

  • Parafibromin loss in mesenchymal progenitors is essential for embryonic organ development.
  • Parafibromin plays a critical role in regulating transcriptional programs in mature osteoblasts, influencing terminal differentiation and bone matrix production.
  • Loss of parafibromin in osteoblasts leads to altered bone remodeling and homeostasis, suggesting its involvement in maintaining skeletal integrity.
Keywords:
Cdc73Hrpt2Osteocyte apoptosisPAF1 complexParafibromin

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