Peroxiredoxin 6 Inhibits Osteogenic Differentiation and Bone Formation Through Human Dental Pulp Stem Cells and Induces Delayed Bone Development

Antioxid Redox Signal. 2019 Jun 10;30(17):1969-1982. doi: 10.1089/ars.2018.7530. Epub 2018 Jun 29.

Abstract

Aims: Peroxiredoxins (PRDXs) are thiol-specific antioxidant enzymes that regulate redox balance that are critical for maintaining the cellular potential for self-renewal and stemness. Stem cell-based regenerative medicine is a promising approach in tissue reconstruction. However, to obtain functional cells for use in clinical applications, stem cell technology still requires improvements. Results: In this study, we found that PRDX6 levels were decreased during osteogenic differentiation in human dental pulp stem cells (hDPSCs). hDPSCs stably expressing Myc-PRDX6 (hDPSC/myc-PRDX6) inhibited cell growth in hDPSCs during osteogenic differentiation and impaired osteogenic phenotypes such as alkaline phosphatase (ALP) activity, mineralized nodule formation, and osteogenic marker genes [ALP and osteocalcin (OCN)]. hDPSC cell lines stably expressing mutant glutathione peroxidase (PRDX6(C47S)) and independent phospholipase A2 (PRDX6(S32A)) were also generated. Each mutant form of PRDX6 abolished the impaired osteogenic phenotypes, the transforming growth factor-β-mediated Smad2 and p38 pathways, and RUNX2 expression. Furthermore, in vivo experiments revealed that hDPSC/myc-PRDX6 suppressed hDPSC-based bone regeneration in calvarial defect mice, and newborn PRDX6 transgenic mice exhibited delayed bone development and reduced RUNX2 expression. Innovation and Conclusion: These findings illuminate the effects of PRDX6 during osteogenic differentiation of hDPSCs, and also suggest that regulating PRDX6 may improve the clinical utility of stem cell-based regenerative medicine for the treatment of bone diseases. Antioxid. Redox Signal. 30, 1969-1982.

Keywords: DPSCs; GPx; PRDX6; bone regeneration; iPLA2; osteogenesis; stem cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Development / genetics*
  • Bone Regeneration / genetics
  • Cell Differentiation / genetics*
  • Cell Proliferation
  • Cells, Cultured
  • Dental Pulp / cytology*
  • Gene Expression
  • Gene Expression Regulation, Developmental
  • Glutathione Peroxidase / metabolism
  • Group VI Phospholipases A2 / metabolism
  • Humans
  • Models, Biological
  • Osteogenesis / genetics*
  • Peroxiredoxin VI / genetics*
  • Peroxiredoxin VI / metabolism
  • Signal Transduction
  • Stem Cells / cytology*
  • Stem Cells / metabolism*
  • Transforming Growth Factor beta / metabolism

Substances

  • Transforming Growth Factor beta
  • Peroxiredoxin VI
  • Glutathione Peroxidase
  • Group VI Phospholipases A2
  • PLA2G6 protein, human