PMID- 22084394
OWN - NLM
STAT- MEDLINE
DCOM- 20120508
LR  - 20220410
IS  - 1468-2060 (Electronic)
IS  - 0003-4967 (Print)
IS  - 0003-4967 (Linking)
VI  - 71
IP  - 4
DP  - 2012 Apr
TI  - Autophagy activation by rapamycin reduces severity of experimental 
      osteoarthritis.
PG  - 575-81
LID - 10.1136/annrheumdis-2011-200557 [doi]
AB  - OBJECTIVES: Osteoarthritis is associated with cell death and extracellular matrix 
      degradation in articular cartilage. Autophagy is an essential cellular 
      homeostasis mechanism that was found to be deficient in ageing and osteoarthritic 
      cartilage. This study determined whether pharmacological inhibition of the 
      mammalian target of rapamycin (mTOR), a key inhibitor of autophagy, has 
      disease-modifying activity in experimental osteoarthritis. METHODS: Experimental 
      osteoarthritis was induced by transection of the medial meniscotibial ligament 
      and the medial collateral ligament in 2-month-old C57Bl/6 mice (n=36). Rapamycin 
      (1 mg/kg weight/day) (n=18 mice) or dimethyl sulphoxide vehicle control (n=18 
      mice) was administered intraperitoneally for 10 weeks. Histopathological changes 
      in articular cartilage and synovium were examined by using semiquantitative 
      scoring systems. Rapamycin effects on mTOR signalling, autophagy, cartilage 
      homeostasis and inflammation were analysed by immunohistochemistry and 
      immunofluorescence staining. RESULTS: Rapamycin affected the mTOR signalling 
      pathway in mouse knee joints as indicated by the inhibition of ribosomal protein 
      S6 phosphorylation, a target of mTOR and activation of LC3, a main marker of 
      autophagy. The severity of cartilage degradation was significantly (p<0.01) 
      reduced in the rapamycin-treated group compared with the control group and this 
      was associated with a significant (p<0.05) decrease in synovitis. Rapamycin 
      treatment also maintained cartilage cellularity and decreased ADAMTS-5 and 
      interleukin-1beta expression in articular cartilage. CONCLUSIONS: These results 
      suggest that rapamycin, at least in part by autophagy activation, reduces the 
      severity of experimental osteoarthritis. Pharmacological activation of autophagy 
      may be an effective therapeutic approach for osteoarthritis.
FAU - Carames, Beatriz
AU  - Carames B
AD  - Department of Molecular and Experimental Medicine, The Scripps Research 
      Institute, La Jolla, California, USA.
FAU - Hasegawa, Akihiko
AU  - Hasegawa A
FAU - Taniguchi, Noboru
AU  - Taniguchi N
FAU - Miyaki, Shigeru
AU  - Miyaki S
FAU - Blanco, Francisco J
AU  - Blanco FJ
FAU - Lotz, Martin
AU  - Lotz M
LA  - eng
GR  - RC2 AR058954-02/AR/NIAMS NIH HHS/United States
GR  - R01 AR056026/AR/NIAMS NIH HHS/United States
GR  - S10 RR027557/RR/NCRR NIH HHS/United States
GR  - RR027577/RR/NCRR NIH HHS/United States
GR  - RC2 AR058954/AR/NIAMS NIH HHS/United States
GR  - S10 RR027557-01/RR/NCRR NIH HHS/United States
GR  - AR058954/AR/NIAMS NIH HHS/United States
GR  - P01 AG007996-18/AG/NIA NIH HHS/United States
GR  - AG007996/AG/NIA NIH HHS/United States
GR  - P01 AG007996/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20111114
PL  - England
TA  - Ann Rheum Dis
JT  - Annals of the rheumatic diseases
JID - 0372355
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Immunosuppressive Agents)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.24.- (ADAM Proteins)
RN  - EC 3.4.24.- (ADAMTS5 Protein)
RN  - EC 3.4.24.- (Adamts5 protein, mouse)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - ADAM Proteins/metabolism
MH  - ADAMTS5 Protein
MH  - Animals
MH  - Anti-Inflammatory Agents/*pharmacology/therapeutic use
MH  - Arthritis, Experimental/*drug therapy/metabolism/pathology
MH  - Autophagy/*drug effects
MH  - Cartilage, Articular/pathology
MH  - Chondrocytes/metabolism
MH  - Drug Evaluation, Preclinical/methods
MH  - Immunosuppressive Agents/pharmacology/therapeutic use
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Osteoarthritis/*drug therapy/metabolism/pathology
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*pharmacology/therapeutic use
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Treatment Outcome
PMC - PMC3294168
MID - NIHMS348383
EDAT- 2011/11/16 06:00
MHDA- 2012/05/09 06:00
PMCR- 2013/04/01
CRDT- 2011/11/16 06:00
PHST- 2011/11/16 06:00 [entrez]
PHST- 2011/11/16 06:00 [pubmed]
PHST- 2012/05/09 06:00 [medline]
PHST- 2013/04/01 00:00 [pmc-release]
AID - annrheumdis-2011-200557 [pii]
AID - 10.1136/annrheumdis-2011-200557 [doi]
PST - ppublish
SO  - Ann Rheum Dis. 2012 Apr;71(4):575-81. doi: 10.1136/annrheumdis-2011-200557. Epub 
      2011 Nov 14.