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LAMP2A regulates the balance of mesenchymal stem cell adipo-osteogenesis via the Wnt/β-catenin/GSK3β signaling pathway

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Abstract

Chaperone-mediated autophagy (CMA) plays multiple roles in cell metabolism. We found that lysosome-associated membrane protein type 2A (LAMP2A), a crucial protein of CMA, plays a key role in the control of mesenchymal stem cell (MSC) adipo-osteogenesis. We identified a differentially expressed CMA gene (LAMP2) in GEO datasets (GSE4911 and GSE494). Further, we performed co-expression analyses to define the relationships between CMA components genes and other relevant genes including Col1a1, Runx2, Wnt3 and Gsk3β. Mouse BMSCs (mMSCs) exhibiting Lamp2a gene knockdown (LA-KD) and overexpression (LA-OE) were created using an adenovirus system; then we investigated LAMP2A function in vitro by Western blot, Oil Red staining, ALP staining, ARS staining and Immunofluorescence analysis. Next, we used a modified mouse model of tibial fracture to investigate LAMP2A function in vivo. LAMP2A knockdown in mMSCs decreased the levels of osteogenic-specific proteins (COL1A1 and RUNX2) and increased those of the adipogenesis markers PPARγ and C/EBPα; LAMP2A overexpression had the opposite effects. The active-β-catenin and phospho-GSK3β (Ser9) levels were upregulated by LAMP2A overexpression and downregulated by LAMP2A knockdown. In the mouse model of tibial fracture, mMSC-overexpressing LAMP2A improved bone healing, as demonstrated by microcomputed tomography and histological analyses. In summary, LAMP2A positively regulates mMSC osteogenesis and suppresses adipo-osteogenesis, probably via Wnt/β-catenin/GSK3β signaling. LAMP2A promoted fracture-healing in the mouse model of tibial fracture.

Key messages

• LAMP2 positively regulates the mBMSCs osteogenic differentiation.

• LAMP2 negatively regulates the mBMSCs adipogenic differentiation.

• LAMP2 regulates mBMSCs osteogenesis via Wnt/β-catenin/GSK3β signaling pathway.

• LAMP2 overexpression mBMSCs promote the fracture healing.

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Data availability statement

The gene expression databases of mice wildtype and RUNX2 knockout humeri (GSE4911-GPL83), human non-union skeletal fracture samples and normal samples (GSE494-GPL92) were downloaded from Gene Expression Omnibus (GEO) datasets. The raw expression data of LAMP2, HSPA8, COL1A1, RUNX2, WNT3 and GSK3B genes were downloaded from the Cancer Cell Line Encyclopedia (CCLE) project (https://portals.broadinstitute.org/ccle), The Cancer Genome Atlas (TCGA) project (http://cancergenome.nih.gov/) and the Genotype Tissue Expression (GTEx) project (https://www.gtexportal.org/).

Abbreviations

BMSCs:

bone marrow mesenchymal stem cells

mMSCs:

mouse bone marrow mesenchymal stem cells

GEO:

Gene Expression Omnibus

DEGs:

differentially expressed genes

KEGG:

Kyoto Encyclopedia of Genes and Genomes

GO:

Gene Ontology

BP:

biological process

CCLE:

the Cancer Cell Line Encyclopedia project

TCGA:

The Cancer Genome Atlas project

GTEx:

the Genotype Tissue Expression project

IHC:

immunohistochemistry

ALP:

alkaline phosphatase

ARS:

alizarin red staining

CMA:

chaperone-mediated autophagy

LAMP2A:

lysosome-associated membrane protein type 2Α

HSPA8:

heat shock protein A8

COL1A1:

collagen type I alpha 1 chain

RUNX2:

runt-related transcription factor 2

OPN:

osteopontin

PPARγ:

peroxisome proliferator-activated receptor gamma

C/EBPα:

CCAAT enhancer binding protein alpha

WNT3:

wnt family member 3

GSK3β:

glycogen synthase kinase 3 beta

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Acknowledgements

We thank the clients who have offered assistance to this study from Clinical Research Center of the second affiliated hospital, Zhejiang university, including Xing Zhang, Meirong Yu, Sicong Chen, Liya Lin, Yunlu Chen, et al. We also appreciate the general help of Linlin Zhang and Shoumin Feng from Orthopedics Research Institute of Zhejiang University.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81874007; 82172404) and the Natural Science Foundation of Zhejiang Province (Y21H070011).

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Author notes

  1. Yibo Wang, Kai Hang, and Li Ying are authors contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopedic Surgery of the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88, Jiefang Road, Hangzhou, 310009, China

    Yibo Wang, Kai Hang, Jiaqi Wu, Xiaoyong Wu, Weijun Zhang, Lijun Li, Zhongxiang Wang, Jinwu Bai, Xiang Gao, Deting Xue & Zhijun Pan

  2. Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou, 310009, China

    Yibo Wang, Kai Hang, Jiaqi Wu, Xiaoyong Wu, Weijun Zhang, Lijun Li, Zhongxiang Wang, Jinwu Bai, Xiang Gao, Deting Xue & Zhijun Pan

  3. Department of Orthopedic, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, No. 150, Ximen Street, Linhai, 317000, China

    Li Ying

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Contributions

XG, DTX and ZJP designed the research; YBW, KH and LY performed the in vitro experiments; YBW, KH, XYW, WJZ, LJL and JWB performed the in vivo experiments; YBW and HK analyzed the data; YBW, KH and XYW wrote the paper; DTX and ZJP revised the paper. All authors have read and approved the manuscript.

Corresponding authors

Correspondence to Xiang Gao, Deting Xue or Zhijun Pan.

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All animal experiments were in accordance to the Animal Care and Use Committee guidelines of Zhejiang University. All experimental procedures were in accordance with the and Institutional Animal Care Use Committee at the Second Affiliated Hospital, School of Medicine, Zhejiang University.

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Wang, Y., Hang, K., Ying, L. et al. LAMP2A regulates the balance of mesenchymal stem cell adipo-osteogenesis via the Wnt/β-catenin/GSK3β signaling pathway. J Mol Med 101, 783–799 (2023). https://doi.org/10.1007/s00109-023-02328-1

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