2. Academic Validation
  3. SCUBE3 promotes osteogenic differentiation and mitophagy in human bone marrow mesenchymal stem cells through the BMP2/TGF-β signaling pathway

SCUBE3 promotes osteogenic differentiation and mitophagy in human bone marrow mesenchymal stem cells through the BMP2/TGF-β signaling pathway

  • FASEB J. 2024 Sep;38(17):e70011. doi: 10.1096/fj.202400991R.
Hongyu Chen 1 2 3 4,  Xiaoyong Wu 1 2 3 4,  Yinan Lan 1 2 3 4,  Xijie Zhou 5,  Ye Zhang 1 2 3 4,  Long Long 1 2 3 4,  Yuliang Zhong 1 2 3 4,  Zhengan Hao 1 2 3 4,  Weijun Zhang 1 2 3 4,  DeTing Xue 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Orthopaedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang, P.R. China.
  • 3 Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang, P.R. China.
  • 4 Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou, P.R. China.
  • 5 The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.
PMID: 39250278 DOI: 10.1096/fj.202400991R
Abstract

In clinical settings, addressing large bone defects remains a significant challenge for orthopedic surgeons. The use of genetically modified bone marrow mesenchymal stem cells (BMSCs) has emerged as a highly promising approach for these treatments. Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a multifunctional secreted glycoprotein, the role of which remains unclear in human hBMSCs. This study used various experimental methods to elucidate the potential mechanism by which SCUBE3 influences osteogenic differentiation of hBMSCs in vitro. Additionally, the therapeutic efficacy of SCUBE3, in conjunction with porous GeLMA microspheres, was evaluated in vivo using a mouse bone defect model. Our findings indicate that SCUBE3 levels increase significantly during early osteogenic differentiation of hBMSCs, and that reducing SCUBE3 levels can hinder this differentiation. Overexpressing SCUBE3 elevated osteogenesis gene and protein levels and enhanced calcium deposition. Furthermore, treatment with recombinant human SCUBE3 (rhSCUBE3) protein boosted BMP2 and TGF-β expression, activated Mitophagy in hBMSCs, ameliorated oxidative stress, and restored osteogenic function through SMAD phosphorylation. In vivo, GELMA/OE treatment effectively accelerated bone healing in mice. In conclusion, SCUBE3 fosters osteogenic differentiation and Mitophagy in hBMSCs by activating the BMP2/TGF-β signaling pathway. When combined with engineered hydrogel cell therapy, it could offer valuable guidance for the clinical management of extensive bone defects.

Keywords

BMP2; HBMSCs; SCUBE3; TGF‐β; mitophagy; osteogenic differentiation.

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