Increased nuclear stiffness via FAK-ERK1/2 signaling is necessary for synthetic mechano-growth factor E peptide-induced tenocyte migration

Sci Rep. 2016 Jan 8:6:18809. doi: 10.1038/srep18809.

Abstract

We have previously reported that a synthetic mechano-growth factor (MGF) C-terminal E-domain with 25 amino acids (MGF-C25E) promotes rat tenocyte migration through the FAK-ERK1/2 signaling pathway. However, the role of the nucleus in MGF-C25E-promoted tenocyte migration and the molecular mechanisms involved remain unclear. In this study, we demonstrate that MGF-C25E increases the Young's modulus of tenocytes through the FAK-ERK1/2 signaling pathway. This increase is not accompanied by an obvious change in the expression of Lamin A/C but is accompanied by significant chromatin condensation, indicating that MGF-C25E-induced chromatin condensation may contribute to the increased nuclear stiffness. Moreover, DNA methylation is observed in MGF-C25E-treated tenocytes. Inhibition of DNA methylation suppresses the elevation in chromatin condensation, in nuclear stiffness, and in tenocyte migration induced by MGF-C25E. The inhibition of the focal adhesion kinase (FAK) or extracellular signal regulated kinase 1/2 (ERK1/2) signals represses MGF-C25E-promoted DNA methylation. It also abolishes chromatin condensation, nuclear stiffness, and cell migration. Taken together, our results suggest that MGF-C25E promotes tenocyte migration by increasing nuclear stiffness via the FAK-ERK1/2 signaling pathway. This provides strong evidence for the role of nuclear mechanics in tenocyte migration and new insight into the molecular mechanisms of MGF-promoted tenocyte migration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement / drug effects
  • Cell Nucleus / chemistry
  • Cell Nucleus / drug effects*
  • Cell Nucleus / metabolism
  • Chromatin / chemistry
  • Chromatin / drug effects
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly / drug effects
  • DNA Methylation / drug effects
  • Flavonoids / pharmacology
  • Focal Adhesion Kinase 1 / genetics*
  • Focal Adhesion Kinase 1 / metabolism
  • Gene Expression Regulation
  • Hardness / drug effects
  • Insulin-Like Growth Factor I / biosynthesis
  • Insulin-Like Growth Factor I / pharmacology*
  • Male
  • Microscopy, Atomic Force
  • Mitogen-Activated Protein Kinase 1 / genetics*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / genetics*
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Primary Cell Culture
  • Protein Domains
  • Protein Kinase Inhibitors / pharmacology
  • Quinolones / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Sulfones / pharmacology
  • Tenocytes / cytology
  • Tenocytes / drug effects*
  • Tenocytes / metabolism

Substances

  • 6-(4-(3-(methylsulfonyl)benzylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one
  • Chromatin
  • Flavonoids
  • Protein Kinase Inhibitors
  • Quinolones
  • Sulfones
  • mechano-growth factor, rat
  • Insulin-Like Growth Factor I
  • Focal Adhesion Kinase 1
  • Ptk2 protein, rat
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one