PMID- 33613450
OWN - NLM
STAT- MEDLINE
DCOM- 20210527
LR  - 20211204
IS  - 1664-2392 (Print)
IS  - 1664-2392 (Electronic)
IS  - 1664-2392 (Linking)
VI  - 11
DP  - 2020
TI  - 17beta-Estradiol Induces Mitophagy Upregulation to Protect Chondrocytes via the 
      SIRT1-Mediated AMPK/mTOR Signaling Pathway.
PG  - 615250
LID - 10.3389/fendo.2020.615250 [doi]
LID - 615250
AB  - Increasing evidence reveals that estrogen, especially 17beta-estradiol (17beta-E2), is 
      associated with articular cartilage metabolism disorder and postmenopausal 
      osteoarthritis (OA). SIRT1, AMPK, and mTOR are regarded as critical mitophagy 
      regulators. Recent studies have shown that mitophagy displays a protective effect 
      against OA, but the molecular mechanism is not well known. This study aimed to 
      investigate the effect of 17beta-E2 on Sirtuin-1 (SIRT1) expression and the 
      induction of mitophagy upregulation by 17beta-E2 via the SIRT1-mediated 
      AMP-activated protein kinase (AMPK)/mammalian target of the rapamycin (mTOR) 
      signaling pathway to protect chondrocytes. ATDC5 chondrocytes were treated with 
      different concentrations of 17beta-E2 (0 M, 1 x 10(-9) M, 1 x 10(-8) M, and 1 x 
      10(-7) M) for 24 h or pretreatment with or without NAM (SIRT1 inhibitor), 
      Compound C (AMPK inhibitor) and S1842 (mTOR inhibitor) for 30 min prior to 
      treatment with 17beta-E2 (1 x 10(-7) M) for 24 in each groups. Expression of SIRT1 
      was evaluated by real-time PCR, Western blotting and confocal immunofluorescence 
      staining. Then, the mitophagosomes in cells were observed under a transmission 
      electron microscopy (TEM), and the AMPK/mTOR signaling pathway was detected by 
      Western blotting. The mitophagy-related proteins, p-AMPK, p-mTOR, p-JNK, and 
      p-p38 were also identified by Western blot analysis. The chondrocytes viability 
      and proliferation were determined by MTT and 5-Bromo-2'-deoxyuridine (BrdU) 
      assay. These experiments were independently repeated 3 times The study found that 
      17beta-E2 increased the expression level of SIRT1, p-AMPK, and mitophagy-related 
      proteins but decreased p-mTOR expression, and then induced mitophagy upregulation 
      in chondrocytes. More mitochondrial autophagosomes were observed in 
      17beta-E2-treated chondrocytes under a transmission electron microscope. Also, 
      17beta-E2 improved cell viability and proliferation with the higher expression of 
      SIRT1 and activation of the AMPK/mTOR signaling pathway. However, SIRT1 inhibitor 
      nicotinamide (NAM) and AMPK inhibitor Compound C blocked the beneficial effect of 
      17beta-E2. In summary, this study was novel in demonstrating that 17beta-E2 induced 
      mitophagy upregulation to protect chondrocytes via the SIRT1-mediated AMPK/mTOR 
      signaling pathway.
CI  - Copyright (c) 2021 Mei, Lou, You, Jiang, Yu and Guo.
FAU - Mei, Runhong
AU  - Mei R
AD  - Department of Orthopaedics, The Fourth Affiliated Hospital of Nanchang 
      University, Nanchang, China.
AD  - Department of Orthopedics, The First Hospital of China Medical University, 
      Shenyang, China.
FAU - Lou, Peng
AU  - Lou P
AD  - Department of Orthopedics, The First Hospital of China Medical University, 
      Shenyang, China.
FAU - You, Guanchao
AU  - You G
AD  - Department of Orthopedics, The First Hospital of China Medical University, 
      Shenyang, China.
FAU - Jiang, Tianlong
AU  - Jiang T
AD  - Department of Orthopedics, The First Hospital of China Medical University, 
      Shenyang, China.
FAU - Yu, Xuefeng
AU  - Yu X
AD  - Department of Orthopaedics, The Fourth Affiliated Hospital of Nanchang 
      University, Nanchang, China.
FAU - Guo, Lei
AU  - Guo L
AD  - Department of Orthopedics, The First Hospital of China Medical University, 
      Shenyang, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210203
PL  - Switzerland
TA  - Front Endocrinol (Lausanne)
JT  - Frontiers in endocrinology
JID - 101555782
RN  - 4TI98Z838E (Estradiol)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - EC 3.5.1.- (SIRT1 protein, human)
RN  - EC 3.5.1.- (Sirtuin 1)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Animals
MH  - Cell Line
MH  - Chondrocytes/drug effects/*metabolism
MH  - Estradiol/*pharmacology
MH  - Humans
MH  - Mitophagy/drug effects/*physiology
MH  - Signal Transduction/drug effects/physiology
MH  - Sirtuin 1/*metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Up-Regulation/drug effects/physiology
PMC - PMC7888342
OTO - NOTNLM
OT  - 17beta-estradiol
OT  - AMP-activated protein kinase/mammalian target of the rapamycin signaling pathway
OT  - Sirtuin-1
OT  - mitophagy
OT  - osteoarthritis
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/02/23 06:00
MHDA- 2021/05/28 06:00
PMCR- 2020/01/01
CRDT- 2021/02/22 05:53
PHST- 2020/10/10 00:00 [received]
PHST- 2020/12/15 00:00 [accepted]
PHST- 2021/02/22 05:53 [entrez]
PHST- 2021/02/23 06:00 [pubmed]
PHST- 2021/05/28 06:00 [medline]
PHST- 2020/01/01 00:00 [pmc-release]
AID - 10.3389/fendo.2020.615250 [doi]
PST - epublish
SO  - Front Endocrinol (Lausanne). 2021 Feb 3;11:615250. doi: 
      10.3389/fendo.2020.615250. eCollection 2020.