Secreted Clusterin protein inhibits osteoblast differentiation of bone marrow mesenchymal stem cells by suppressing ERK1/2 signaling pathway

Basem Abdallah, Abdullah M Alzahrani, Moustapha Kassem

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Resumé

Secreted Clusterin (sCLU, also known as Apolipoprotein J) is an anti-apoptotic glycoprotein involved in the regulation of cell proliferation, lipid transport, extracellular tissue remodeling and apoptosis. sCLU is expressed and secreted by mouse bone marrow-derived skeletal (stromal or mesenchymal) stem cells (mBMSCs), but its functional role in MSC biology is not known. In this study, we demonstrated that Clusterin mRNA expression and protein secretion in conditioned medium increased during adipocyte differentiation and decreased during osteoblast differentiation of mBMSCs. Treatment of mBMSC cultures with recombinant sCLU protein increased cell proliferation and exerted an inhibitory effect on the osteoblast differentiation while stimulated adipocyte differentiation in a dose-dependent manner. siRNA-mediated silencing of Clu expression in mBMSCs reduced adipocyte differentiation and stimulated osteoblast differentiation of mBMSCs. Furthermore, the inhibitory effect of sCLU on the osteoblast differentiation of mBMSCs was mediated by the suppression of extracellular signal-regulated kinase (ERK1/2) phosphorylation. In conclusion, we identified sCLU as a regulator of mBMSCs lineage commitment to osteoblasts versus adipocytes through a mechanism mediated by ERK1/2 signaling. Inhibiting sCLU is a possible therapeutic approach for enhancing osteoblast differentiation and consequently bone formation.
OriginalsprogEngelsk
TidsskriftBone
Vol/bind110
Sider (fra-til)221-229
ISSN8756-3282
DOI
StatusUdgivet - maj 2018

Fingeraftryk

Clusterin
MAP Kinase Signaling System
Osteoblasts
Mesenchymal Stromal Cells
Adipocytes
Proteins
Cell Proliferation
Mitogen-Activated Protein Kinase 1
Conditioned Culture Medium
Recombinant Proteins
Osteogenesis
Small Interfering RNA
Apoptosis
Lipids
Messenger RNA

Citer dette

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title = "Secreted Clusterin protein inhibits osteoblast differentiation of bone marrow mesenchymal stem cells by suppressing ERK1/2 signaling pathway",
abstract = "Secreted Clusterin (sCLU, also known as Apolipoprotein J) is an anti-apoptotic glycoprotein involved in the regulation of cell proliferation, lipid transport, extracellular tissue remodeling and apoptosis. sCLU is expressed and secreted by mouse bone marrow-derived skeletal (stromal or mesenchymal) stem cells (mBMSCs), but its functional role in MSC biology is not known. In this study, we demonstrated that Clusterin mRNA expression and protein secretion in conditioned medium increased during adipocyte differentiation and decreased during osteoblast differentiation of mBMSCs. Treatment of mBMSC cultures with recombinant sCLU protein increased cell proliferation and exerted an inhibitory effect on the osteoblast differentiation while stimulated adipocyte differentiation in a dose-dependent manner. siRNA-mediated silencing of Clu expression in mBMSCs reduced adipocyte differentiation and stimulated osteoblast differentiation of mBMSCs. Furthermore, the inhibitory effect of sCLU on the osteoblast differentiation of mBMSCs was mediated by the suppression of extracellular signal-regulated kinase (ERK1/2) phosphorylation. In conclusion, we identified sCLU as a regulator of mBMSCs lineage commitment to osteoblasts versus adipocytes through a mechanism mediated by ERK1/2 signaling. Inhibiting sCLU is a possible therapeutic approach for enhancing osteoblast differentiation and consequently bone formation.",
keywords = "Computational biology, Developmental neurotoxicity, Pesticide, Pyriproxyfen, Predictive toxicology, Systems biology, Toxicity testing, Adipocyte, sCLU, Clusterin, Osteoblast differentiation, Osteoblast, BMSCs, Mesenchymal stem cells, Male, Mesenchymal Stem Cells/cytology, Signal Transduction/physiology, Osteoblasts/cytology, Cell Differentiation/physiology, MAP Kinase Signaling System/physiology, Enzyme-Linked Immunosorbent Assay, Mice, Inbred C57BL, Cells, Cultured, Blotting, Western, Adipocytes/cytology, Animals, Alkaline Phosphatase/genetics, Mice, Clusterin/metabolism",
author = "Basem Abdallah and Alzahrani, {Abdullah M} and Moustapha Kassem",
year = "2018",
month = "5",
doi = "10.1016/j.bone.2018.02.018",
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Secreted Clusterin protein inhibits osteoblast differentiation of bone marrow mesenchymal stem cells by suppressing ERK1/2 signaling pathway. / Abdallah, Basem; Alzahrani, Abdullah M; Kassem, Moustapha.

I: Bone, Bind 110, 05.2018, s. 221-229.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Secreted Clusterin protein inhibits osteoblast differentiation of bone marrow mesenchymal stem cells by suppressing ERK1/2 signaling pathway

AU - Abdallah, Basem

AU - Alzahrani, Abdullah M

AU - Kassem, Moustapha

PY - 2018/5

Y1 - 2018/5

N2 - Secreted Clusterin (sCLU, also known as Apolipoprotein J) is an anti-apoptotic glycoprotein involved in the regulation of cell proliferation, lipid transport, extracellular tissue remodeling and apoptosis. sCLU is expressed and secreted by mouse bone marrow-derived skeletal (stromal or mesenchymal) stem cells (mBMSCs), but its functional role in MSC biology is not known. In this study, we demonstrated that Clusterin mRNA expression and protein secretion in conditioned medium increased during adipocyte differentiation and decreased during osteoblast differentiation of mBMSCs. Treatment of mBMSC cultures with recombinant sCLU protein increased cell proliferation and exerted an inhibitory effect on the osteoblast differentiation while stimulated adipocyte differentiation in a dose-dependent manner. siRNA-mediated silencing of Clu expression in mBMSCs reduced adipocyte differentiation and stimulated osteoblast differentiation of mBMSCs. Furthermore, the inhibitory effect of sCLU on the osteoblast differentiation of mBMSCs was mediated by the suppression of extracellular signal-regulated kinase (ERK1/2) phosphorylation. In conclusion, we identified sCLU as a regulator of mBMSCs lineage commitment to osteoblasts versus adipocytes through a mechanism mediated by ERK1/2 signaling. Inhibiting sCLU is a possible therapeutic approach for enhancing osteoblast differentiation and consequently bone formation.

AB - Secreted Clusterin (sCLU, also known as Apolipoprotein J) is an anti-apoptotic glycoprotein involved in the regulation of cell proliferation, lipid transport, extracellular tissue remodeling and apoptosis. sCLU is expressed and secreted by mouse bone marrow-derived skeletal (stromal or mesenchymal) stem cells (mBMSCs), but its functional role in MSC biology is not known. In this study, we demonstrated that Clusterin mRNA expression and protein secretion in conditioned medium increased during adipocyte differentiation and decreased during osteoblast differentiation of mBMSCs. Treatment of mBMSC cultures with recombinant sCLU protein increased cell proliferation and exerted an inhibitory effect on the osteoblast differentiation while stimulated adipocyte differentiation in a dose-dependent manner. siRNA-mediated silencing of Clu expression in mBMSCs reduced adipocyte differentiation and stimulated osteoblast differentiation of mBMSCs. Furthermore, the inhibitory effect of sCLU on the osteoblast differentiation of mBMSCs was mediated by the suppression of extracellular signal-regulated kinase (ERK1/2) phosphorylation. In conclusion, we identified sCLU as a regulator of mBMSCs lineage commitment to osteoblasts versus adipocytes through a mechanism mediated by ERK1/2 signaling. Inhibiting sCLU is a possible therapeutic approach for enhancing osteoblast differentiation and consequently bone formation.

KW - Computational biology

KW - Developmental neurotoxicity

KW - Pesticide

KW - Pyriproxyfen

KW - Predictive toxicology

KW - Systems biology

KW - Toxicity testing

KW - Adipocyte

KW - sCLU

KW - Clusterin

KW - Osteoblast differentiation

KW - Osteoblast

KW - BMSCs

KW - Mesenchymal stem cells

KW - Male

KW - Mesenchymal Stem Cells/cytology

KW - Signal Transduction/physiology

KW - Osteoblasts/cytology

KW - Cell Differentiation/physiology

KW - MAP Kinase Signaling System/physiology

KW - Enzyme-Linked Immunosorbent Assay

KW - Mice, Inbred C57BL

KW - Cells, Cultured

KW - Blotting, Western

KW - Adipocytes/cytology

KW - Animals

KW - Alkaline Phosphatase/genetics

KW - Mice

KW - Clusterin/metabolism

U2 - 10.1016/j.bone.2018.02.018

DO - 10.1016/j.bone.2018.02.018

M3 - Journal article

C2 - 29476977

VL - 110

SP - 221

EP - 229

JO - Bone

JF - Bone

SN - 8756-3282

ER -