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Cell cycle exit during bortezomib-induced osteogenic differentiation of mesenchymal stem cells was mediated by

Dan Zhang1, Rong Fan1, Li Lei1

  • 1Department of Cell Biology and Genetics, Xi'an Jiaotong University Health Science Center, Xi'an, China.

Journal of Cellular and Molecular Medicine
|July 7, 2020
PubMed

Insights

Low doses of bortezomib promote osteogenic differentiation in mesenchymal stem cells (MSCs) by arresting the cell cycle. This process involves ER stress signaling, upregulating key inhibitors like p21 and p27.

Area of Science:

  • Cell Biology
  • Stem Cell Research
  • Pharmacology

Background:

  • Mesenchymal stem cells (MSCs) are multipotent and crucial for bone regeneration.
  • Bortezomib, a proteasome inhibitor, treats multiple myeloma and aids bone disease by inducing osteoblast differentiation.
  • Understanding bortezomib's impact on MSCs' cell cycle during osteogenesis is vital.

Purpose of the Study:

  • Investigate bortezomib's effects on the cell cycle during osteogenic differentiation of MSCs.
  • Elucidate the molecular mechanisms underlying bortezomib-induced cell cycle changes.
  • Explore the role of ER stress signaling in this process.

Main Methods:

  • Treatment of MSCs with varying bortezomib doses.
  • Analysis of cell cycle progression (G0/G1 arrest).
  • Assessment of proliferation rates and expression of cyclin-dependent kinase inhibitors (p21Cip1, p27Kip1).
  • Investigation of the ER stress pathway (Ire1α/Xbp1s).

Main Results:

  • Low-dose bortezomib induced osteogenic differentiation in MSCs.
  • Bortezomib treatment led to G0/G1 cell cycle arrest and reduced proliferation.
  • Upregulation of p21Cip1 and p27Kip1 correlated with cell cycle exit.
  • This upregulation was dependent on the Ire1α/Xbp1s ER stress pathway.

Conclusions:

  • Bortezomib at low doses drives MSC osteogenic differentiation via cell cycle arrest.
  • The Ire1α/Xbp1s ER stress pathway mediates bortezomib's effects on cell cycle regulators.
  • This pathway links proteasome inhibition, osteogenesis, and cell cycle control.
Keywords:
Xbp1sbortezomibcell cyclemesenchymal stem cellsp21Cip1p27Kip1

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