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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.
OriginalsprogEngelsk
TidsskriftJournal of Biological Chemistry
Vol/bind286
Udgave nummer37
Sider (fra-til)32140-9
Antal sider10
ISSN0021-9258
DOI
StatusUdgivet - 2011

Fingeraftryk

Cell Differentiation
Phosphotransferases
Antigens
Chondrogenesis
Fibronectins
Phosphatidylinositol 3-Kinases
Collagen Type X
Chemical activation
Aggrecans
Collagen Type II
Conditioned Culture Medium
Osteoblasts
Cartilage
Adipocytes
p38 Mitogen-Activated Protein Kinases
Small Interfering RNA
Gene expression
Insulin

Citer dette

Chen, Li ; Qanie, Diyako ; Jafari, Abbas ; Taipaleenmaki, Hanna ; Jensen, Charlotte H ; Säämänen, Anna-Marja ; Sanz, Maria Luisa Nueda ; Laborda, Jorge ; Abdallah, Basem M ; Kassem, Moustapha. / Delta-like 1/fetal antigen-1 (Dlk1/FA1) is a novel regulator of chondrogenic cell differentiation via inhibition of the Akt kinase-dependent pathway. I: Journal of Biological Chemistry. 2011 ; Bind 286, Nr. 37. s. 32140-9.
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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.",
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author = "Li Chen and Diyako Qanie and Abbas Jafari and Hanna Taipaleenmaki and Jensen, {Charlotte H} and Anna-Marja S{\"a}{\"a}m{\"a}nen and Sanz, {Maria Luisa Nueda} and Jorge Laborda and Abdallah, {Basem M} and Moustapha Kassem",
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Delta-like 1/fetal antigen-1 (Dlk1/FA1) is a novel regulator of chondrogenic cell differentiation via inhibition of the Akt kinase-dependent pathway. / Chen, Li; Qanie, Diyako; Jafari, Abbas; Taipaleenmaki, Hanna; Jensen, Charlotte H; Säämänen, Anna-Marja; Sanz, Maria Luisa Nueda; Laborda, Jorge; Abdallah, Basem M; Kassem, Moustapha.

I: Journal of Biological Chemistry, Bind 286, Nr. 37, 2011, s. 32140-9.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Delta-like 1/fetal antigen-1 (Dlk1/FA1) is a novel regulator of chondrogenic cell differentiation via inhibition of the Akt kinase-dependent pathway

AU - Chen, Li

AU - Qanie, Diyako

AU - Jafari, Abbas

AU - Taipaleenmaki, Hanna

AU - Jensen, Charlotte H

AU - Säämänen, Anna-Marja

AU - Sanz, Maria Luisa Nueda

AU - Laborda, Jorge

AU - Abdallah, Basem M

AU - Kassem, Moustapha

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

KW - Aggrecans

KW - Animals

KW - Cell Differentiation

KW - Cell Line

KW - Cell Proliferation

KW - Chondrogenesis

KW - Collagen Type II

KW - Collagen Type X

KW - Embryonic Stem Cells

KW - Enzyme Activation

KW - Fibronectins

KW - Intercellular Signaling Peptides and Proteins

KW - MAP Kinase Signaling System

KW - Mice

KW - Mitogen-Activated Protein Kinase 3

KW - Phosphatidylinositol 3-Kinases

KW - Proto-Oncogene Proteins c-akt

KW - p38 Mitogen-Activated Protein Kinases

U2 - 10.1074/jbc.M111.230110

DO - 10.1074/jbc.M111.230110

M3 - Journal article

C2 - 21724852

VL - 286

SP - 32140

EP - 32149

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 37

ER -