PMID- 34403508
OWN - NLM
STAT- MEDLINE
DCOM- 20210909
LR  - 20210909
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Linking)
VI  - 35
IP  - 9
DP  - 2021 Sep
TI  - Induced senescence of healthy nucleus pulposus cells is mediated by paracrine 
      signaling from TNF-alpha-activated cells.
PG  - e21795
LID - 10.1096/fj.202002201R [doi]
AB  - Intervertebral disc degeneration is an irreversible process associated with 
      accumulation of senescent nucleus pulposus (NP) cells. This study investigates 
      the hypothesis that Tumor necrosis factor-alpha (TNF-alpha)-treated senescent NP cells 
      propagate senescence of neighboring healthy cells via a paracrine effect that 
      involves p-Stat3 signaling and the cytokine interleukin-6 (IL-6). NP cells 
      isolated from bovine caudal intervertebral disc (IVD) were treated with TNF-alpha to 
      induce senescence which was confirmed by demonstrating upregulation of 
      senescence-associated beta-galactosidase and p16. This was correlated with 
      downregulation of NP-associated markers, Aggrecan, Col2A1, and Sox9. Direct 
      contact and non-contact co-culture of healthy and senescent cells showed that 
      TNF-alpha-treated cells increased the senescence in healthy cells via a paracrine 
      effect. The senescent cells have a secretory phenotype as indicated by increased 
      gene and protein levels of IL-6. Phosphorylated Signal Transducer and Activator 
      of Transcription 3 (pStat3) levels were also high in treated cells and appeared 
      to upregulate IL-6 as inhibition of Stat3 phosphorylation by StatticV 
      downregulated IL-6 mRNA expression in cells and protein levels in the culture 
      media. All trans retinoic acid, an IL-6 inhibitor, also decreased the secretion 
      of IL-6 and reduced the paracrine effect of senescent cells on healthy cells. 
      Decreased pStat3 levels and inhibition of IL-6 secretion did not fully restore NP 
      gene expression of Col2A1 but importantly, appeared to cause senescent cells to 
      undergo apoptosis and cell death. This study demonstrated the paracrine effect of 
      senescent NP cells which involves Stat3 and IL-6 and may explain why senescent NP 
      cells accumulate in IVD with age. The role of pSTAT3 and IL-6 in mediating NP 
      senescence requires further study as it may be a novel strategy for modulating 
      the senescent-inducing effects of TNF-alpha.
CI  - (c) 2021 Federation of American Societies for Experimental Biology.
FAU - Ashraf, Sajjad
AU  - Ashraf S
AD  - Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
FAU - Santerre, Paul
AU  - Santerre P
AD  - Institute of Biomaterials and Biomedical Engineering, University of Toronto, ON, 
      Canada.
FAU - Kandel, Rita
AU  - Kandel R
AD  - Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
AD  - Institute of Biomaterials and Biomedical Engineering, University of Toronto, ON, 
      Canada.
AD  - Pathology and Laboratory Medicine, Sinai Health System, Toronto, ON, Canada.
AD  - Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
LA  - eng
GR  - MOP-142325/CIHR/Canada
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 (Interleukin-6)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Cattle
MH  - Cell Death/drug effects
MH  - Cellular Senescence/*drug effects
MH  - Gene Expression Regulation/drug effects
MH  - Interleukin-6/antagonists & inhibitors/metabolism
MH  - Nucleus Pulposus/*cytology/*drug effects/metabolism
MH  - Paracrine Communication/*drug effects
MH  - Phosphorylation
MH  - STAT3 Transcription Factor/metabolism
MH  - Tumor Necrosis Factor-alpha/*pharmacology
OTO - NOTNLM
OT  - IL-6
OT  - STAT3
OT  - TNF-alpha
OT  - intervertebral disc
OT  - paracrine effect
OT  - senescence
EDAT- 2021/08/18 06:00
MHDA- 2021/09/10 06:00
CRDT- 2021/08/17 17:20
PHST- 2021/05/27 00:00 [revised]
PHST- 2020/11/03 00:00 [received]
PHST- 2021/06/28 00:00 [accepted]
PHST- 2021/08/17 17:20 [entrez]
PHST- 2021/08/18 06:00 [pubmed]
PHST- 2021/09/10 06:00 [medline]
AID - 10.1096/fj.202002201R [doi]
PST - ppublish
SO  - FASEB J. 2021 Sep;35(9):e21795. doi: 10.1096/fj.202002201R.