PMID- 27118398
OWN - NLM
STAT- MEDLINE
DCOM- 20180501
LR  - 20181202
IS  - 1522-9653 (Electronic)
IS  - 1063-4584 (Print)
IS  - 1063-4584 (Linking)
VI  - 24
IP  - 9
DP  - 2016 Sep
TI  - Suppression of REDD1 in osteoarthritis cartilage, a novel mechanism for 
      dysregulated mTOR signaling and defective autophagy.
PG  - 1639-47
LID - S1063-4584(16)30050-4 [pii]
LID - 10.1016/j.joca.2016.04.015 [doi]
AB  - OBJECTIVE: Aging is a main risk factor for the development of osteoarthritis (OA) 
      and the molecular mechanisms underlying the aging-related changes in articular 
      cartilage include increased mammalian target of rapamycin (mTOR) signaling and 
      defective autophagy. REDD1 is an endogenous inhibitor of mTOR that regulates 
      cellular stress responses. In this study we measured REDD1 expression in normal, 
      aged and OA cartilage and assessed REDD1 function in human and mouse articular 
      chondrocytes. METHODS: REDD1 expression was analyzed in human and mouse articular 
      cartilage by qPCR, western blotting, and immunohistochemistry. For functional 
      studies, REDD1 and TXNIP knockdown or overexpression was performed in 
      chondrocytes in the presence or absence of rapamycin and chloroquine, and mTOR 
      signaling and autophagy were measured by western blotting. REDD1/TXNIP protein 
      interaction was assessed by co-immunoprecipitation experiments. RESULTS: Human 
      and mouse cartilage from normal knee joints expressed high levels of REDD1. REDD1 
      expression was significantly reduced in aged and OA cartilage. In cultured 
      chondrocytes, REDD1 knockdown increased whereas REDD1 overexpression decreased 
      mTOR signaling. In addition, REDD1 activated autophagy by an mTOR independent 
      mechanism that involved protein/protein interaction with TXNIP. The REDD1/TXNIP 
      complex was required for autophagy activation in chondrocytes. CONCLUSION: The 
      present study shows that REDD1 is highly expressed in normal human articular 
      cartilage and reduced during aging and OA. REDD1 in human chondrocytes negatively 
      regulates mTOR activity and is essential for autophagy activation. Reduced REDD1 
      expression thus represents a novel mechanism for the increased mTOR activation 
      and defective autophagy observed in OA.
CI  - Copyright (c) 2016 Osteoarthritis Research Society International. Published by 
      Elsevier Ltd. All rights reserved.
FAU - Alvarez-Garcia, O
AU  - Alvarez-Garcia O
AD  - Department of Molecular and Experimental Medicine, The Scripps Research 
      Institute, La Jolla, CA, USA.
FAU - Olmer, M
AU  - Olmer M
AD  - Department of Molecular and Experimental Medicine, The Scripps Research 
      Institute, La Jolla, CA, USA.
FAU - Akagi, R
AU  - Akagi R
AD  - Department of Molecular and Experimental Medicine, The Scripps Research 
      Institute, La Jolla, CA, USA; Department of Orthopaedic Surgery, School of 
      Medicine, Chiba University, 1-8-1, Inohana, Chuou, Chiba, 260-8677, Japan.
FAU - Akasaki, Y
AU  - Akasaki Y
AD  - Department of Molecular and Experimental Medicine, The Scripps Research 
      Institute, La Jolla, CA, USA.
FAU - Fisch, K M
AU  - Fisch KM
AD  - Department of Molecular and Experimental Medicine, The Scripps Research 
      Institute, La Jolla, CA, USA.
FAU - Shen, T
AU  - Shen T
AD  - Department of Molecular and Experimental Medicine, The Scripps Research 
      Institute, La Jolla, CA, USA.
FAU - Su, A I
AU  - Su AI
AD  - Department of Molecular and Experimental Medicine, The Scripps Research 
      Institute, La Jolla, CA, USA.
FAU - Lotz, M K
AU  - Lotz MK
AD  - Department of Molecular and Experimental Medicine, The Scripps Research 
      Institute, La Jolla, CA, USA. Electronic address: mlotz@scripps.edu.
LA  - eng
GR  - P01 AG007996/AG/NIA NIH HHS/United States
GR  - R01 AG049617/AG/NIA NIH HHS/United States
GR  - UL1 TR001114/TR/NCATS NIH HHS/United States
PT  - Journal Article
DEP - 20160423
PL  - England
TA  - Osteoarthritis Cartilage
JT  - Osteoarthritis and cartilage
JID - 9305697
SB  - IM
MH  - Animals
MH  - Autophagy
MH  - Cartilage, Articular
MH  - Cells, Cultured
MH  - Chondrocytes
MH  - Humans
MH  - Mice
MH  - *Osteoarthritis
MH  - Signal Transduction
PMC - PMC4992644
MID - NIHMS791169
OTO - NOTNLM
OT  - Autophagy
OT  - Cartilage
OT  - Osteoarthritis
OT  - REDD1
OT  - mTOR
COIS- The authors have no conflicts of interest.
EDAT- 2016/04/28 06:00
MHDA- 2018/05/02 06:00
PMCR- 2017/09/01
CRDT- 2016/04/28 06:00
PHST- 2015/11/11 00:00 [received]
PHST- 2016/04/09 00:00 [revised]
PHST- 2016/04/18 00:00 [accepted]
PHST- 2016/04/28 06:00 [entrez]
PHST- 2016/04/28 06:00 [pubmed]
PHST- 2018/05/02 06:00 [medline]
PHST- 2017/09/01 00:00 [pmc-release]
AID - S1063-4584(16)30050-4 [pii]
AID - 10.1016/j.joca.2016.04.015 [doi]
PST - ppublish
SO  - Osteoarthritis Cartilage. 2016 Sep;24(9):1639-47. doi: 
      10.1016/j.joca.2016.04.015. Epub 2016 Apr 23.