PMID- 34910686
OWN - NLM
STAT- MEDLINE
DCOM- 20220131
LR  - 20220131
IS  - 1945-4589 (Electronic)
IS  - 1945-4589 (Linking)
VI  - 13
IP  - 24
DP  - 2021 Dec 15
TI  - METTL14 benefits the mesenchymal stem cells in patients with steroid-associated 
      osteonecrosis of the femoral head by regulating the m6A level of PTPN6.
PG  - 25903-25919
LID - 10.18632/aging.203778 [doi]
AB  - Imbalanced osteogenic/adipogenic differentiation of bone marrow mesenchymal stem 
      cells (BMSCs) is considered the core pathological characteristic of 
      steroid-associated osteonecrosis of the femoral head (SONFH). N6-Methyladenosine 
      (m6A) is the most common type of RNA modification in eukaryotic cells and 
      participates in various physiological and pathological processes. However, the 
      relationship between m6A modification and SONFH has not been reported. In the 
      present study, we aimed to explore the roles of m6A modifications and 
      methyltransferase METTL14 in SONFH. Our results showed that the m6A levels were 
      down-regulated in femoral head tissues and BMSCs from SONFH patients, and this 
      effect was attributed to the reduction of METTL14. Furthermore, METTL14 
      overexpression in BMSCs from SONFH patients enhanced cell proliferation and 
      osteogenic differentiation. We further identified PTPN6 as the downstream target 
      of METTL14 by mRNA sequencing. Mechanistically, METTL14 regulated PTPN6 
      expression by increasing PTPN6 mRNA stability in an m6A-dependent manner. 
      Moreover, PTPN6 knockdown abrogated the beneficial effects of METTL14 
      overexpression on BMSCs. Additionally, we found that METTL14 activated the Wnt 
      signaling pathway, and this effect was caused by the interaction of PTPN6 and 
      GSK-3beta. In conclusion, we elucidated the functional roles of METTL14 and m6A 
      methylation in SONFH BMSCs and identified a novel RNA regulatory mechanism, 
      providing a potential therapeutic target for SONFH.
FAU - Cheng, Cheng
AU  - Cheng C
AD  - Department of Orthopedics, Henan Provincial People's Hospital, Zhengzhou, Henan, 
      China.
FAU - Zhang, Haoping
AU  - Zhang H
AD  - Department of Mini-invasive Spinal Surgery, Third Hospital of Henan Province, 
      Zhengzhou, Henan, China.
FAU - Zheng, Jia
AU  - Zheng J
AD  - Department of Orthopedics, Henan Provincial People's Hospital, Zhengzhou, Henan, 
      China.
FAU - Jin, Yi
AU  - Jin Y
AD  - Department of Orthopedics, Henan Provincial People's Hospital, Zhengzhou, Henan, 
      China.
FAU - Wang, Donghui
AU  - Wang D
AD  - Department of Orthopedics, Henan Provincial People's Hospital, Zhengzhou, Henan, 
      China.
FAU - Dai, Zhipeng
AU  - Dai Z
AD  - Department of Orthopedics, Henan Provincial People's Hospital, Zhengzhou, Henan, 
      China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211215
PL  - United States
TA  - Aging (Albany NY)
JT  - Aging
JID - 101508617
RN  - 0 (Steroids)
RN  - CLE6G00625 (N-methyladenosine)
RN  - EC 2.1.1.- (METTL14 protein, human)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 3.1.3.48 (PTPN6 protein, human)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 6)
RN  - K72T3FS567 (Adenosine)
SB  - IM
MH  - Adenosine/*analogs & derivatives/metabolism
MH  - Bone Marrow/metabolism
MH  - Cell Differentiation
MH  - Cell Proliferation
MH  - *Femur Head/metabolism/physiology
MH  - Glycogen Synthase Kinase 3 beta/metabolism
MH  - Humans
MH  - Mesenchymal Stem Cells/*metabolism
MH  - Methyltransferases/*genetics
MH  - Osteogenesis/drug effects
MH  - *Osteonecrosis/chemically induced/genetics
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 6/*genetics
MH  - Steroids/adverse effects
PMC - PMC8751613
OTO - NOTNLM
OT  - METTL14
OT  - Wnt signaling pathway
OT  - m6A
OT  - mesenchymal stem cell
OT  - osteonecrosis of the femoral head
COIS- CONFLICTS OF INTEREST: The authors declare no conflicts of interest related to 
      this study.
EDAT- 2021/12/16 06:00
MHDA- 2022/02/01 06:00
PMCR- 2021/12/31
CRDT- 2021/12/15 17:16
PHST- 2021/06/18 00:00 [received]
PHST- 2021/11/22 00:00 [accepted]
PHST- 2021/12/16 06:00 [pubmed]
PHST- 2022/02/01 06:00 [medline]
PHST- 2021/12/15 17:16 [entrez]
PHST- 2021/12/31 00:00 [pmc-release]
AID - 203778 [pii]
AID - 10.18632/aging.203778 [doi]
PST - ppublish
SO  - Aging (Albany NY). 2021 Dec 15;13(24):25903-25919. doi: 10.18632/aging.203778. 
      Epub 2021 Dec 15.