title: Delta-like 1/fetal antigen-1 (Dlk1/FA1) is a novel regulator of chondrogenic cell differentiation via inhibition of the Akt kinase-dependent pathway.
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.
authors: Molecular Endocrinology Laboratory, Odense University Hospital, University of Southern Denmark, Odense DK-5000, Denmark.
authors: Li
authors: L
authors: Chen
authors: Diyako
authors: D
authors: Qanie
authors: Abbas
authors: A
authors: Jafari
authors: Hanna
authors: H
authors: Taipaleenmaki
authors: Charlotte H
authors: CH
authors: Jensen
authors: Anna-Marja
authors: AM
authors: Säämänen
authors: Maria Luisa Nueda
authors: ML
authors: Sanz
authors: Jorge
authors: J
authors: Laborda
authors: Basem M
authors: BM
authors: Abdallah
authors: Moustapha
authors: M
authors: Kassem
mesh_terms: D053674:Aggrecans / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D020219:Chondrogenesis / Q000502:physiology*; D024043:Collagen Type II / Q000096:biosynthesis / Q000235:genetics; D024121:Collagen Type X / Q000096:biosynthesis / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation; D005353:Fibronectins / Q000096:biosynthesis / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D053674:Aggrecans; D002135:Calcium-Binding Proteins; D024043:Collagen Type II; D024121:Collagen Type X; D005353:Fibronectins; D036341:Intercellular Signaling Peptides and Proteins; D048052:Mitogen-Activated Protein Kinase 3; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C512925:Dlk1 protein, mouse