Loss of β-Actin Leads to Accelerated Mineralization and Dysregulation of Osteoblast-Differentiation Genes during Osteogenic Reprogramming

Tamara Gjorgjieva, Xin Xie, Patrick Commins, Renu Pasricha, Syed Raza Mahmood, Kristin C. Gunsalus, Panče Naumov, Piergiorgio Percipalle

Research output: Contribution to journalArticlepeer-review

Abstract

Actin plays fundamental roles in both the cytoplasm and the cell nucleus. In the nucleus, β-actin regulates neuronal reprogramming by consolidating a heterochromatin landscape required for transcription of neuronal gene programs, yet it remains unknown whether it has a role in other differentiation models. To explore the potential roles of β-actin in osteogenesis, β-actin wild-type (WT) and β-actin knockout (KO) mouse embryonic fibroblasts (MEFs) are reprogrammed to osteoblast-like cells using small molecules in vitro. It is discovered that loss of β-actin leads to an accelerated mineralization phenotype (hypermineralization), accompanied with enhanced formation of extracellular hydroxyapatite microcrystals, which originate in the mitochondria in the form of microgranules. This phenotype is a consequence of rapid upregulation of mitochondrial genes including those involved in oxidative phosphorylation (OXPHOS) in reprogrammed KO cells. It is further found that osteogenic gene programs are differentially regulated between WT and KO cells, with clusters of genes exhibiting different temporal expression patterns. A novel function for β-actin in osteogenic reprogramming through a mitochondria-based mechanism that controls cell-mediated mineralization is proposed.

Original languageEnglish (US)
JournalAdvanced Science
DOIs
StateAccepted/In press - 2020

Keywords

  • mineralization
  • mitochondria
  • osteogenesis
  • transcriptional reprogramming
  • β-actin

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Chemical Engineering(all)
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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