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Terbium promotes adhesion and osteogenic differentiation of mesenchymal stem cells via activation of the Smad-dependent TGF-β/BMP signaling pathway

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Abstract

With its special physical and chemical properties, terbium has been widely used, which has inevitably increased the chance of human exposure to terbium-based compounds. It was reported that terbium mainly deposited in bone after introduction into the human body. Although some studies revealed the effects of terbium on bone cell lines, there have been few reports about the potential effect of terbium on adhesion and differentiation of mesenchymal stem cells (MSCs). In this study, we investigated the effects of terbium on the adhesion and osteogenic and adipogenic differentiation of MSCs and the associated molecular mechanisms. Our data reveal that terbium promoted the osteogenic differentiation in a time-dependent manner and conversely inhibited the adipogenic differentiation of MSCs. Meanwhile, the cell–cell or cell–matrix interaction was enhanced by activating adherent-related key factors, which were evaluated by real-time reverse transcriptase polymerase chain reaction (RT-PCR). Real-time RT-PCR and Western blot analysis were also performed to further detect osteogenic and adipogenic biomarkers of MSCs. The regulation of terbium on differentiation of MSCs led to the interaction between the transforming growth factor β/bone morphogenetic protein and peroxisome-proliferator-activated receptor γ (PPARγ) signaling pathways, resulting in upregulation of the osteogenic master transcription factors, such as Runt-related transcription factor 2, bone morphogenetic protein 2, collagen I, alkaline phosphatase, and osteocalcin, and downregulation of the adipogenic master transcription factors, such as PPARγ2. The results provide novel evidence to elucidate the mechanisms of bone metabolism by terbium and may be helpful for more rational application of terbium-based compounds in the future.

Graphical abstract

The effects of terbium on the osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs) and the associated molecular mechanisms were investigated. The results suggest that terbium promotes the osteogenic differentiation of MSCs via the transforming growth factor β (TGFβ)/bone morphogenetic protein (BMP) signaling pathway. ALP alkaline phosphatase, BSP bone sialoprotein, C/EBP CCAAT/enhancer binding protein, Col I collagen I, ERα estrogen receptor α, GDF growth differentiation factor, OCN osteocalcin, PPARγ peroxisome-proliferator-activated receptor γ, Runx2 Runt-related transcription factor 2

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Abbreviations

ALP:

Alkaline phosphatase

AS:

Adipogenic induction supplement

BMP:

Bone morphogenetic protein

cDNA:

Complementary DNA

C/EBPα:

CCAAT/enhancer binding protein α

C/EBPβ:

CCAAT/enhancer binding protein β

C/EBPδ:

CCAAT/enhancer binding protein δ

DMEM:

Dulbecco’s modified Eagle’s medium

GDF:

Growth differentiation factor

HGF:

Hepatocyte growth factor

MCAM:

Melanoma cell adhesion molecule

MSC:

Mesenchymal stem cell

MTT:

3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide

OD:

Optical density

OS:

Osteogenic induction supplement

PBS:

Phosphate-buffered saline

PCR:

Polymerase chain reaction

PPARγ:

Peroxisome-proliferator-activated receptor γ

p-Smad1/5/8:

Phosphorylated Smad1/5/8

RT-PCR:

Reverse transcriptase polymerase chain reaction

Runx2:

Runt-related transcription factor 2

SEM:

Scanning electron microscope

TBST:

10 mM tris(hydroxymethyl)aminomethane–HCl pH 8.0, 150 mM NaCl, 0.05 % Tween 20

TGF-β:

Transforming growth factor β

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (nos. 21271059 and 20971034), Research Fund for the Doctoral Program of Higher Education of China (No. 20111301110004), Hundred Excellent Innovation Talents Supporting Project of Hebei Province (BR2-201), and Training Program for Innovative Research Team and Leading Talent in Hebei Province University (LJRC024).

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Authors and Affiliations

  1. College of Chemistry and Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding, 071002, People’s Republic of China

    Dan-Dan Liu, Kun Ge, Yi Jin, Shu-Xiang Wang & Jin-Chao Zhang

  2. Department of B-Ultrasound, Affiliated Hospital, Hebei University, Baoding, 071000, People’s Republic of China

    Jing Sun

  3. Department of Biology and Chemistry, City University of Hong Kong, Hong Kong, People’s Republic of China

    Meng-Su Yang

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  1. Dan-Dan Liu
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  2. Kun Ge
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  3. Yi Jin
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  4. Jing Sun
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  5. Shu-Xiang Wang
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  7. Jin-Chao Zhang
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Correspondence to Jin-Chao Zhang.

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D.-D. Liu and K. Ge contributed equally.

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Liu, DD., Ge, K., Jin, Y. et al. Terbium promotes adhesion and osteogenic differentiation of mesenchymal stem cells via activation of the Smad-dependent TGF-β/BMP signaling pathway. J Biol Inorg Chem 19, 879–891 (2014). https://doi.org/10.1007/s00775-014-1119-4

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  • DOI: https://doi.org/10.1007/s00775-014-1119-4

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