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Metastasis suppressor 1 controls osteoblast differentiation and bone homeostasis through regulating Src-Wnt/β-catenin signaling

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Abstract

Metastasis suppressor 1 (MTSS1) plays an inhibitory role in tumorigenesis and metastasis of a variety of cancers. To date, the function of MTSS1 in the differentiation of marrow stromal progenitor cells remains to be explored. In the current study, we investigated whether and how MTSS1 has a role in osteoblast differentiation and bone homeostasis. Our data showed that MTSS1 mRNA was upregulated during osteoblast differentiation and downregulated in the osteoblastic lineage cells of ovariectomized and aged mice. Functional studies revealed that MTSS1 promoted the osteogenic differentiation from marrow stromal progenitor cells. Mechanistic explorations uncovered that the inactivation of Src and afterward activation of canonical Wnt signaling were involved in osteoblast differentiation induced by MTSS1. The enhanced osteogenic differentiation induced by MTSS1 overexpression was attenuated when Src was simultaneously overexpressed, and conversely, the inhibition of osteogenic differentiation by MTSS1 siRNA was rescued when the Src inhibitor was supplemented to the culture. Finally, the in vivo transfection of MTSS1 siRNA to the marrow of mice significantly reduced the trabecular bone mass, along with the reduction of trabecular osteoblasts, the accumulation of marrow adipocytes, and the increase of phospho-Src-positive cells on the trabeculae. No change in the number of osteoclasts was observed. This study has unraveled that MTSS1 contributes to osteoblast differentiation and bone homeostasis through regulating Src-Wnt/β-catenin signaling. It also suggests the potential of MTSS1 as a new target for the treatment of osteoporosis.

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Availability of data and material

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

ALP:

Alkaline phosphatase

BMP2:

Bone morphogenetic protein 2

BMSCs:

Bone marrow mesenchymal stem cells

C/EBP:

CCAAT/enhancer binding protein

FBS:

Fetal bovine serum

GSK3β:

Glycogen synthase kinase 3β

HRP:

Horseradish peroxidase

LRP6:

Low-density lipoprotein receptor-related protein 6

MTSS1:

Metastasis suppressor 1

OPN:

Osteopontin

PPARγ:

Peroxisome proliferator-activated receptor γ

Quantitative reverse transcription polymerase chain reaction:

QRT-PCR

Runx2:

Runt-related transcription factor 2

siRNA:

Small interfering RNA

TCF7L2:

Transcription factor 7-like 2

TRAP:

Tartrate-resistant acid phosphatase

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Acknowledgements

The authors thank the National Natural Science Foundation of China (NSFC) and Natural Science Foundation of Tianjin City for funding.

Funding

This work was funded by National Natural Science Foundation of China (81871741, 82072389, 81972033, and 81972031) and by Natural Science Foundation of Tianjin City (19JCYBJC25400).

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Author notes

  1. Meng Chen and Liying Shan contributed equally to the work.

Authors and Affiliations

  1. NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Institute of Endocrinology, Tianjin Medical University, 6 Huan-Rui-Bei Road, Tianjin, 300134, China

    Meng Chen, Liying Shan, Ying Gan, Lijie Tian, Jie Zhou, Endong Zhu, Hairui Yuan & Baoli Wang

  2. College of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China

    Xiaoxia Li

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  1. Meng Chen
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Contributions

MC, LS, YG, and LT performed the experiments. JZ, EZ, and HY analyzed the data. XL supervised the research. BW designed the study, supervised the research, and wrote the manuscript. All the authors read and approved the final manuscript.

Corresponding author

Correspondence to Baoli Wang.

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The authors declare that they have no competing interests.

Ethical approval

The animal experiments were carried out following the National Standard of Animal Care and Use Procedures, and was approved by the Animal Ethics Committee of Tianjin Medical University Chu Hsien-I Memorial Hospital.

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Chen, M., Shan, L., Gan, Y. et al. Metastasis suppressor 1 controls osteoblast differentiation and bone homeostasis through regulating Src-Wnt/β-catenin signaling. Cell. Mol. Life Sci. 79, 107 (2022). https://doi.org/10.1007/s00018-022-04147-y

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  • DOI: https://doi.org/10.1007/s00018-022-04147-y

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