Plasminogen Activator inhibitor-1 Deficiency Suppresses Osteoblastic Differentiation of Mesenchymal Stem Cells in Mice

J Cell Physiol. 2019 Jun;234(6):9687-9697. doi: 10.1002/jcp.27655. Epub 2018 Nov 1.

Abstract

Plasminogen activator inhibitor-1 (PAI-1) is known as an inhibitor of fibrinolytic system. Previous studies suggest that PAI-1 is involved in the pathogenesis of osteoporosis induced by ovariectomy, diabetes, and glucocorticoid excess in mice. However, the roles of PAI-1 in early-stage osteogenic differentiation have remained unknown. In the current study, we investigated the roles of PAI-1 in osteoblastic differentiation of mesenchymal stem cells (MSCs) using wild-type (WT) and PAI-1-deficient (PAI-1 KO) mice. PAI-1 mRNA levels were increased with time during osteoblastic differentiation of MSCs or mesenchymal ST-2 cells. However, the increased PAI-1 levels declined at the mineralization phase in the experiment using MC3T3-E1 cells. PAI-1 deficiency significantly blunted the expression of osteogenic gene, such as osterix and alkaline phosphatase enhanced by bone morphogenetic protein (BMP)-2 in bone marrow-derived MSCs (BM-MSCs), adipose-tissue-derived MSCs (AD-MSCs), and bone marrow stromal cells of mice. Moreover, a reduction in endogenous PAI-1 levels by small interfering RNA significantly suppressed the expression of osteogenic gene in ST-2 cells. Plasmin did not affect osteoblastic differentiation of AD-MSCs induced by BMP-2 with or without PAI-1 deficiency. PAI-1 deficiency and a reduction in endogenous PAI-1 levels did not affect the phosphorylations of receptor-specific Smads by BMP-2 and transforming growth factor-β in AD-MSCs and ST-2 cells, respectively. In conclusion, we first showed that PAI-1 is crucial for the differentiation of MSCs into osteoblasts in mice.

Keywords: mesenchymal stem cell; osteoblastic differentiation; plasminogen activator inhibitor-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / metabolism
  • Cell Differentiation* / drug effects
  • Cell Line
  • Fibrinolysin / pharmacology
  • Fibrinolysis / drug effects
  • Hemorrhagic Disorders / metabolism*
  • Hemorrhagic Disorders / pathology*
  • Male
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Osteoblasts / pathology*
  • Osteogenesis / drug effects
  • Phosphorylation / drug effects
  • Plasminogen Activator Inhibitor 1 / deficiency*
  • Plasminogen Activator Inhibitor 1 / metabolism*
  • Signal Transduction / drug effects
  • Smad Proteins / metabolism

Substances

  • Bone Morphogenetic Proteins
  • Plasminogen Activator Inhibitor 1
  • Smad Proteins
  • Fibrinolysin

Supplementary concepts

  • Plasminogen Activator Inhibitor-1 Deficiency