2. Academic Validation
  3. LAMP2A regulates the balance of mesenchymal stem cell adipo-osteogenesis via the Wnt/β-catenin/GSK3β signaling pathway

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

  • J Mol Med (Berl). 2023 May 10. doi: 10.1007/s00109-023-02328-1.
Yibo Wang # 1 2,  Kai Hang # 1 2,  Li Ying # 3,  Jiaqi Wu 1 2,  Xiaoyong Wu 1 2,  Weijun Zhang 1 2,  Lijun Li 1 2,  Zhongxiang Wang 1 2,  Jinwu Bai 1 2,  Xiang Gao 4 5,  Deting Xue 6 7,  Zhijun Pan 8 9
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery of the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88, Jiefang Road, Hangzhou, 310009, China.
  • 2 Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou, 310009, China.
  • 3 Department of Orthopedic, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, No. 150, Ximen Street, Linhai, 317000, China.
  • 4 Department of Orthopedic Surgery of the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88, Jiefang Road, Hangzhou, 310009, China. gaoxiang162@zju.edu.cn.
  • 5 Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou, 310009, China. gaoxiang162@zju.edu.cn.
  • 6 Department of Orthopedic Surgery of the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88, Jiefang Road, Hangzhou, 310009, China. blueskine@zju.edu.cn.
  • 7 Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou, 310009, China. blueskine@zju.edu.cn.
  • 8 Department of Orthopedic Surgery of the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88, Jiefang Road, Hangzhou, 310009, China. zrpzj@zju.edu.cn.
  • 9 Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou, 310009, China. zrpzj@zju.edu.cn.
  • # Contributed equally.
PMID: 37162558 DOI: 10.1007/s00109-023-02328-1
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.

Keywords

Adipogenesis; CMA; LAMP2A; Osteogenesis; Wnt/β-catenin/GSK3β; mMSCs.

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