PMID- 37144883
OWN - NLM
STAT- MEDLINE
DCOM- 20230508
LR  - 20230513
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Linking)
VI  - 37
IP  - 6
DP  - 2023 Jun
TI  - MFG-E8 promotes osteogenic differentiation of human bone marrow mesenchymal stem 
      cells through GSK3beta/beta-catenin signaling pathway.
PG  - e22950
LID - 10.1096/fj.202201417RRR [doi]
AB  - Fracture nonunion and bone defects are challenging for orthopedic surgeons. Milk 
      fat globule-epidermal growth factor 8 (MFG-E8), a glycoprotein possibly secreted 
      by macrophages in a fracture hematoma, participates in bone development. However, 
      the role of MFG-E8 in the osteogenic differentiation of bone marrow mesenchymal 
      stem cells (BMSCs) is unclear. We investigated the osteogenic effect of MFG-E8 in 
      vitro and in vivo. The CCK-8 assay was used to assess the effect of recombinant 
      human MFG-E8 (rhMFG-E8) on the viability of hBMSCs. Osteogenesis was investigated 
      using RT-PCR, Western blotting, and immunofluorescence. Alkaline phosphatase 
      (ALP) and Alizarin red staining were used to evaluate ALP activity and 
      mineralization, respectively. An enzyme-linked immunosorbent assay was conducted 
      to evaluate the secretory MFG-E8 concentration. Knockdown and overexpression of 
      MFG-E8 in hBMSCs were established via siRNA and lentivirus vector transfection, 
      respectively. Exogenous rhMFG-E8 was used to verify the in vivo therapeutic 
      effect in a tibia bone defect model based on radiographic analysis and 
      histological evaluation. Endogenous and secretory MFG-E8 levels increased 
      significantly during the early osteogenic differentiation of hBMSCs. Knockdown of 
      MFG-E8 inhibited the osteogenic differentiation of hBMSCs. Overexpression of 
      MFG-E8 and rhMFG-E8 protein increased the expression of osteogenesis-related 
      genes and proteins and enhanced calcium deposition. The active beta-catenin to total 
      beta-catenin ratio and the p-GSK3beta protein level were increased by MFG-E8. The 
      MFG-E8-induced enhanced osteogenic differentiation of hBMSCs was partially 
      attenuated by a GSK3beta/beta-catenin signaling inhibitor. Recombinant MFG-E8 
      accelerated bone healing in a rat tibial-defect model. In conclusion, MFG-E8 
      promotes the osteogenic differentiation of hBMSCs by regulating the 
      GSK3beta/beta-catenin signaling pathway and so, is a potential therapeutic target.
CI  - (c) 2023 Federation of American Societies for Experimental Biology.
FAU - Bai, Jinwu
AU  - Bai J
AD  - Department of Orthopaedics, The Second Affiliated Hospital, Zhejiang University 
      School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
AD  - Orthopedics Research Institute, Zhejiang University, Hangzhou, People's Republic 
      of China.
AD  - Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang 
      Province, Hangzhou City, Zhejiang Province, PR China.
AD  - Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou 
      City, Zhejiang Province, PR China.
FAU - Zhang, Weijun
AU  - Zhang W
AD  - Department of Orthopaedics, The Second Affiliated Hospital, Zhejiang University 
      School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
AD  - Orthopedics Research Institute, Zhejiang University, Hangzhou, People's Republic 
      of China.
AD  - Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang 
      Province, Hangzhou City, Zhejiang Province, PR China.
AD  - Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou 
      City, Zhejiang Province, PR China.
FAU - Zhou, Chenwei
AU  - Zhou C
AD  - Department of Orthopaedics, The Second Affiliated Hospital, Zhejiang University 
      School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
AD  - Orthopedics Research Institute, Zhejiang University, Hangzhou, People's Republic 
      of China.
AD  - Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang 
      Province, Hangzhou City, Zhejiang Province, PR China.
AD  - Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou 
      City, Zhejiang Province, PR China.
FAU - Zhao, Guangfeng
AU  - Zhao G
AD  - Department of Emergency, The Second Affiliated Hospital, Zhejiang University 
      School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
FAU - Zhong, Huiming
AU  - Zhong H
AD  - Department of Emergency, The Second Affiliated Hospital, Zhejiang University 
      School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
FAU - Hang, Kai
AU  - Hang K
AD  - Department of Orthopaedics, The Second Affiliated Hospital, Zhejiang University 
      School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
AD  - Orthopedics Research Institute, Zhejiang University, Hangzhou, People's Republic 
      of China.
AD  - Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang 
      Province, Hangzhou City, Zhejiang Province, PR China.
AD  - Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou 
      City, Zhejiang Province, PR China.
FAU - Xu, Jianxiang
AU  - Xu J
AD  - Department of Orthopaedics, The Second Affiliated Hospital, Zhejiang University 
      School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
AD  - Orthopedics Research Institute, Zhejiang University, Hangzhou, People's Republic 
      of China.
AD  - Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang 
      Province, Hangzhou City, Zhejiang Province, PR China.
AD  - Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou 
      City, Zhejiang Province, PR China.
FAU - Zhang, Wei
AU  - Zhang W
AD  - Department of Orthopaedics, The Second Affiliated Hospital, Zhejiang University 
      School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
AD  - Orthopedics Research Institute, Zhejiang University, Hangzhou, People's Republic 
      of China.
AD  - Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang 
      Province, Hangzhou City, Zhejiang Province, PR China.
AD  - Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou 
      City, Zhejiang Province, PR China.
FAU - Chen, Erman
AU  - Chen E
AD  - Department of Orthopaedics, The Second Affiliated Hospital, Zhejiang University 
      School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
AD  - Orthopedics Research Institute, Zhejiang University, Hangzhou, People's Republic 
      of China.
AD  - Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang 
      Province, Hangzhou City, Zhejiang Province, PR China.
AD  - Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou 
      City, Zhejiang Province, PR China.
FAU - Wu, Jiaqi
AU  - Wu J
AD  - Department of Orthopaedics, The Second Affiliated Hospital, Zhejiang University 
      School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
AD  - Orthopedics Research Institute, Zhejiang University, Hangzhou, People's Republic 
      of China.
AD  - Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang 
      Province, Hangzhou City, Zhejiang Province, PR China.
AD  - Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou 
      City, Zhejiang Province, PR China.
FAU - Liu, Ling
AU  - Liu L
AD  - Department of Nephrology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese 
      Medical University, Hangzhou, People's Republic of China.
FAU - Xue, Deting
AU  - Xue D
AD  - Department of Orthopaedics, The Second Affiliated Hospital, Zhejiang University 
      School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
AD  - Orthopedics Research Institute, Zhejiang University, Hangzhou, People's Republic 
      of China.
AD  - Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang 
      Province, Hangzhou City, Zhejiang Province, PR China.
AD  - Clinical Research Center of Motor System Disease of Zhejiang Province, Hangzhou 
      City, Zhejiang Province, PR China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (milk fat globule)
RN  - 0 (beta Catenin)
RN  - 9001-27-8 (Factor VIII)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - 0 (Glycoproteins)
SB  - IM
MH  - Humans
MH  - Rats
MH  - Animals
MH  - *Osteogenesis/physiology
MH  - beta Catenin/genetics/metabolism
MH  - Factor VIII/metabolism/pharmacology
MH  - Glycogen Synthase Kinase 3 beta/genetics/metabolism
MH  - Signal Transduction/physiology
MH  - Cell Differentiation/physiology
MH  - Glycoproteins/metabolism
MH  - *Mesenchymal Stem Cells/metabolism
MH  - Cells, Cultured
MH  - Wnt Signaling Pathway
MH  - Bone Marrow Cells/metabolism
OTO - NOTNLM
OT  - MFG-E8
OT  - Wnt/beta-catenin
OT  - hBMSCs
OT  - osteogenesis
OT  - osteogenic differentiation
EDAT- 2023/05/05 12:42
MHDA- 2023/05/08 10:17
CRDT- 2023/05/05 09:02
PHST- 2023/04/13 00:00 [revised]
PHST- 2022/08/30 00:00 [received]
PHST- 2023/04/25 00:00 [accepted]
PHST- 2023/05/08 10:17 [medline]
PHST- 2023/05/05 12:42 [pubmed]
PHST- 2023/05/05 09:02 [entrez]
AID - 10.1096/fj.202201417RRR [doi]
PST - ppublish
SO  - FASEB J. 2023 Jun;37(6):e22950. doi: 10.1096/fj.202201417RRR.