PMID- 28334504
OWN - NLM
STAT- MEDLINE
DCOM- 20170821
LR  - 20201230
IS  - 2326-5205 (Electronic)
IS  - 2326-5191 (Print)
IS  - 2326-5191 (Linking)
VI  - 69
IP  - 7
DP  - 2017 Jul
TI  - Regulated in Development and DNA Damage Response 1 Deficiency Impairs Autophagy 
      and Mitochondrial Biogenesis in Articular Cartilage and Increases the Severity of 
      Experimental Osteoarthritis.
PG  - 1418-1428
LID - 10.1002/art.40104 [doi]
AB  - OBJECTIVE: Regulated in development and DNA damage response 1 (REDD1) is an 
      endogenous inhibitor of mechanistic target of rapamycin (mTOR) that regulates 
      cellular stress responses. REDD1 expression is decreased in aged and 
      osteoarthritic (OA) cartilage, and it regulates mTOR signaling and autophagy in 
      articular chondrocytes in vitro. This study was undertaken to investigate the 
      effects of REDD1 deletion in vivo using a mouse model of experimental OA. 
      METHODS: OA severity was histologically assessed in 4-month-old wild-type and 
      REDD1(-/-) mice subjected to surgical destabilization of the medial meniscus 
      (DMM). Chondrocyte autophagy, apoptosis, mitochondrial content, and expression of 
      mitochondrial biogenesis markers were determined in cartilage and cultured 
      chondrocytes from wild-type and REDD1(-/-) mice. RESULTS: REDD1 deficiency 
      increased the severity of changes in cartilage, menisci, subchondral bone, and 
      synovium in the DMM model of OA. Chondrocyte death was increased in the cartilage 
      of REDD1(-/-) mice and in cultured REDD1(-/-) mouse chondrocytes under oxidative 
      stress conditions. Expression of key autophagy markers (microtubule-associated 
      protein 1A/1B light chain 3 and autophagy protein 5) was markedly reduced in 
      cartilage from REDD1(-/-) mice and in cultured human and mouse chondrocytes with 
      REDD1 depletion. Mitochondrial content, ATP levels, and expression of the 
      mitochondrial biogenesis markers peroxisome proliferator-activated receptor gamma 
      coactivator 1alpha (PGC-1alpha) and transcription factor A, mitochondrial (TFAM) were 
      also decreased in REDD1-deficient chondrocytes. REDD1 was required for 
      AMP-activated protein kinase-induced PGC-1alpha in chondrocytes. CONCLUSION: Our 
      findings suggest that REDD1 is a key mediator of cartilage homeostasis through 
      regulation of autophagy and mitochondrial biogenesis and that REDD1 deficiency 
      exacerbates the severity of injury-induced OA.
CI  - (c) 2017, American College of Rheumatology.
FAU - Alvarez-Garcia, Oscar
AU  - Alvarez-Garcia O
AD  - The Scripps Research Institute, La Jolla, California.
FAU - Matsuzaki, Tokio
AU  - Matsuzaki T
AD  - The Scripps Research Institute, La Jolla, California.
FAU - Olmer, Merissa
AU  - Olmer M
AD  - The Scripps Research Institute, La Jolla, California.
FAU - Plate, Lars
AU  - Plate L
AD  - The Scripps Research Institute, La Jolla, California.
FAU - Kelly, Jeffery W
AU  - Kelly JW
AD  - The Scripps Research Institute, La Jolla, California.
FAU - Lotz, Martin K
AU  - Lotz MK
AD  - The Scripps Research Institute, La Jolla, California.
LA  - eng
GR  - P01 AG007996/AG/NIA NIH HHS/United States
GR  - R01 AG049617/AG/NIA NIH HHS/United States
PT  - Journal Article
DEP - 20170602
PL  - United States
TA  - Arthritis Rheumatol
JT  - Arthritis & rheumatology (Hoboken, N.J.)
JID - 101623795
RN  - 0 (Autophagy-Related Protein 5)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Ddit4 protein, mouse)
RN  - 0 (High Mobility Group Proteins)
RN  - 0 (MAP1A protein, mouse)
RN  - 0 (Map1lc3b protein, mouse)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Ppargc1a protein, mouse)
RN  - 0 (Tfam protein, mouse)
RN  - 0 (Transcription Factors)
RN  - 0 (microtubule-associated protein 1B)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Animals
MH  - Apoptosis/*genetics
MH  - Arthritis, Experimental/*genetics/metabolism
MH  - Autophagy/*genetics
MH  - Autophagy-Related Protein 5/metabolism
MH  - Cartilage, Articular/*metabolism
MH  - Chondrocytes/*metabolism
MH  - DNA-Binding Proteins/metabolism
MH  - Disease Models, Animal
MH  - High Mobility Group Proteins/metabolism
MH  - Humans
MH  - Immunohistochemistry
MH  - Menisci, Tibial/surgery
MH  - Mice
MH  - Mice, Knockout
MH  - Microtubule-Associated Proteins/metabolism
MH  - Mitochondria/metabolism
MH  - Organelle Biogenesis
MH  - Osteoarthritis, Knee/*genetics/metabolism
MH  - Oxidative Stress
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
MH  - Synovial Membrane/metabolism
MH  - Transcription Factors/*genetics
PMC - PMC5489357
MID - NIHMS861258
COIS- The authors have no conflicts of interest.
EDAT- 2017/03/24 06:00
MHDA- 2017/08/22 06:00
PMCR- 2018/07/01
CRDT- 2017/03/24 06:00
PHST- 2016/09/27 00:00 [received]
PHST- 2017/03/16 00:00 [accepted]
PHST- 2017/03/24 06:00 [pubmed]
PHST- 2017/08/22 06:00 [medline]
PHST- 2017/03/24 06:00 [entrez]
PHST- 2018/07/01 00:00 [pmc-release]
AID - 10.1002/art.40104 [doi]
PST - ppublish
SO  - Arthritis Rheumatol. 2017 Jul;69(7):1418-1428. doi: 10.1002/art.40104. Epub 2017 
      Jun 2.