Delta-like 1/fetal antigen-1 (Dlk1/FA1) is a novel regulator of chondrogenic cell differentiation via inhibition of the Akt kinase-dependent pathway

Li Chen, Diyako Qanie, Abbas Jafari, Hanna Taipaleenmaki, Charlotte H Jensen, Anna-Marja Säämänen, Maria Luisa Nueda Sanz, Jorge Laborda, Basem M Abdallah, Moustapha Kassem

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Abstract

Delta-like 1 (Dlk1, also known as fetal antigen-1, FA1) is a member of Notch/Delta family that inhibits adipocyte and osteoblast differentiation; however, its role in chondrogenesis is still not clear. Thus, we overexpressed Dlk1/FA1 in mouse embryonic ATDC5 cells and tested its effects on chondrogenic differentiation. Dlk1/FA1 inhibited insulin-induced chondrogenic differentiation as evidenced by reduction of cartilage nodule formation and gene expression of aggrecan, collagen Type II and X. Similar effects were obtained either by using Dlk1/FA1-conditioned medium or by addition of a purified, secreted, form of Dlk1 (FA1) directly to the induction medium. The inhibitory effects of Dlk1/FA1 were dose-dependent and occurred irrespective of the chondrogenic differentiation stage: proliferation, differentiation, maturation, or hypertrophic conversion. Overexpression or addition of the Dlk1/FA1 protein to the medium strongly inhibited the activation of Akt, but not the ERK1/2, or p38 MAPK pathways, and the inhibition of Akt by Dlk1/FA1 was mediated through PI3K activation. Interestingly, inhibition of fibronectin expression by siRNA rescued the Dlk1/FA1-mediated inhibition of Akt, suggesting interaction of Dlk1/FA1 and fibronectin in chondrogenic cells. Our results identify Dlk1/FA1 as a novel regulator of chondrogenesis and suggest Dlk1/FA1 acts as an inhibitor of the PI3K/Akt pathways that leads to its inhibitory effects on chondrogenesis.
Original languageEnglish
JournalJournal of Biological Chemistry
Volume286
Issue number37
Pages (from-to)32140-9
Number of pages10
ISSN0021-9258
DOIs
Publication statusPublished - 2011

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Keywords

  • Aggrecans
  • Animals
  • Cell Differentiation
  • Cell Line
  • Cell Proliferation
  • Chondrogenesis
  • Collagen Type II
  • Collagen Type X
  • Embryonic Stem Cells
  • Enzyme Activation
  • Fibronectins
  • Intercellular Signaling Peptides and Proteins
  • MAP Kinase Signaling System
  • Mice
  • Mitogen-Activated Protein Kinase 3
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases

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