PMID- 34536393
OWN - NLM
STAT- MEDLINE
DCOM- 20211108
LR  - 20211204
IS  - 1872-7786 (Electronic)
IS  - 0009-2797 (Linking)
VI  - 349
DP  - 2021 Nov 1
TI  - Fluoride regulates chondrocyte proliferation and autophagy via PI3K/AKT/mTOR 
      signaling pathway.
PG  - 109659
LID - S0009-2797(21)00297-0 [pii]
LID - 10.1016/j.cbi.2021.109659 [doi]
AB  - Fluorine is an essential trace element for human health. However, excessive 
      fluoride intake causes skeletal fluorosis which affects cartilage development. 
      Fluoride inhibited chondrocyte proliferation which is the initial and critical 
      step of endochondral ossification, but the underlying mechanism has not been 
      clearly illustrated. Mammalian target of rapamycin (mTOR) is an important protein 
      kinase which modulates various cellular processes and is believed to be a central 
      regulator of chondrocyte proliferation and autophagy. In this study, we explored 
      the effect of fluoride on the proliferation and autophagy of chondrocytes and the 
      regulatory role of mTOR signaling pathway. Our results suggested that NaF 
      inhibited the protein expressions of proliferating cell nuclear antigen (PCNA) 
      and pS6 in cultured fetal rat tibias. Furthermore, NaF significantly 
      downregulated the expressions of mTOR signaling pathway-related genes, including 
      PI3K, AKT, mTOR, 4EBP1 and S6K1 in mouse ATDC5 chondrogenic cell line. We also 
      found that NaF increased autophagy in ATDC5 cells. The mRNA and protein levels of 
      autophagy-related genes LC3, Beclin1 and p62 were significantly changed after NaF 
      treatment. Further studies demonstrated that MHY1485, a small-molecular mTOR 
      activator, totally reversed fluoride-induced promotion of autophagy. MHY1485 also 
      recovered the downregulation of proliferative chondrocytes markers Sox9 and Type 
      Ⅱ Collagen (Col2a1) induced by fluoride in ATDC5 cells. Taken together, our 
      result demonstrate that fluoride suppressed proliferation and facilitated 
      autophagy via PI3K/AKT/mTOR signaling pathway in chondrogenesis.
CI  - Copyright (c) 2021 Elsevier B.V. All rights reserved.
FAU - Ma, Lan
AU  - Ma L
AD  - Department of Environmental Health, School of Public Health, China Medical 
      University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 
      Province, PR China.
FAU - Zhang, Ruixue
AU  - Zhang R
AD  - Department of Environmental Health, School of Public Health, China Medical 
      University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 
      Province, PR China.
FAU - Li, Demin
AU  - Li D
AD  - Department of Environmental Health, School of Public Health, China Medical 
      University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 
      Province, PR China.
FAU - Qiao, Tingting
AU  - Qiao T
AD  - Department of Environmental Health, School of Public Health, China Medical 
      University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 
      Province, PR China.
FAU - Guo, Xiaoying
AU  - Guo X
AD  - Department of Environmental Health, School of Public Health, China Medical 
      University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 
      Province, PR China. Electronic address: guoxy@cmu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20210916
PL  - Ireland
TA  - Chem Biol Interact
JT  - Chemico-biological interactions
JID - 0227276
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - Q80VPU408O (Fluorides)
SB  - IM
MH  - Autophagy/*drug effects
MH  - Cell Proliferation/*drug effects
MH  - Chondrocytes/cytology/*drug effects
MH  - Fluorides/*pharmacology
MH  - Humans
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases/*metabolism
OTO - NOTNLM
OT  - ATDC5 cells
OT  - Autophagy
OT  - Fluoride
OT  - Proliferation
OT  - mTOR
EDAT- 2021/09/19 06:00
MHDA- 2021/11/09 06:00
CRDT- 2021/09/18 20:10
PHST- 2021/05/01 00:00 [received]
PHST- 2021/08/17 00:00 [revised]
PHST- 2021/09/14 00:00 [accepted]
PHST- 2021/09/19 06:00 [pubmed]
PHST- 2021/11/09 06:00 [medline]
PHST- 2021/09/18 20:10 [entrez]
AID - S0009-2797(21)00297-0 [pii]
AID - 10.1016/j.cbi.2021.109659 [doi]
PST - ppublish
SO  - Chem Biol Interact. 2021 Nov 1;349:109659. doi: 10.1016/j.cbi.2021.109659. Epub 
      2021 Sep 16.