PMID- 20506288
OWN - NLM
STAT- MEDLINE
DCOM- 20100903
LR  - 20211203
IS  - 1529-0131 (Electronic)
IS  - 0004-3591 (Linking)
VI  - 62
IP  - 8
DP  - 2010 Aug
TI  - Mammalian target of rapamycin signaling is crucial for joint destruction in 
      experimental arthritis and is activated in osteoclasts from patients with 
      rheumatoid arthritis.
PG  - 2294-302
LID - 10.1002/art.27504 [doi]
AB  - OBJECTIVE: Activation of the mammalian target of rapamycin (mTOR) pathway is 
      important for immune cell activation and bone metabolism. To date, the 
      contribution of mTOR signaling to joint inflammation and structural bone and 
      cartilage damage is unknown. The aim of this study was to investigate the 
      potential of inhibiting mTOR as a treatment of inflammatory arthritis. METHODS: 
      Human tumor necrosis factor-transgenic mice in which inflammatory arthritis was 
      developing were treated with 2 different mTOR inhibitors, sirolimus or 
      everolimus. The effects of treatment on clinical disease activity, inflammation, 
      and localized joint and cartilage destruction were studied. In addition, the 
      effects of mTOR inhibition on osteoclast survival and expression of key molecules 
      of osteoclast function were analyzed in vitro. Moreover, synovial tissue from 
      patients with rheumatoid arthritis (RA) was assessed for activation of the mTOR 
      pathway. RESULTS: Inhibition of mTOR by sirolimus or everolimus reduced synovial 
      osteoclast formation and protected against local bone erosions and cartilage 
      loss. Clinical signs of arthritis improved after mTOR inhibition, and histologic 
      evaluation showed a decrease in synovitis. In vitro, mTOR inhibition 
      down-regulated the expression of digestive enzymes and led to osteoclast 
      apoptosis. Moreover, mTOR signaling was shown to be active in the synovial 
      membrane of patients with RA, particularly in synovial osteoclasts. CONCLUSION: 
      Signaling through mTOR is an important link between synovitis and structural 
      damage in inflammatory arthritis. Current pharmacologic inhibitors of mTOR could 
      be effective in protecting joints against structural damage.
FAU - Cejka, Daniel
AU  - Cejka D
AD  - Medical University of Vienna, Vienna, Austria.
FAU - Hayer, Silvia
AU  - Hayer S
FAU - Niederreiter, Birgit
AU  - Niederreiter B
FAU - Sieghart, Wolfgang
AU  - Sieghart W
FAU - Fuereder, Thorsten
AU  - Fuereder T
FAU - Zwerina, Jochen
AU  - Zwerina J
FAU - Schett, Georg
AU  - Schett G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Arthritis Rheum
JT  - Arthritis and rheumatism
JID - 0370605
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Tumor Necrosis Factors)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Arthritis, Experimental/drug therapy/*metabolism/pathology
MH  - Arthritis, Rheumatoid/*metabolism/pathology
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Everolimus
MH  - Humans
MH  - Immunohistochemistry
MH  - Immunosuppressive Agents/pharmacology/therapeutic use
MH  - Inflammation/metabolism/pathology
MH  - Intracellular Signaling Peptides and Proteins/*metabolism
MH  - Joints/metabolism/*pathology
MH  - Mice
MH  - Mice, Transgenic
MH  - Osteoclasts/drug effects/*metabolism/pathology
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Signal Transduction
MH  - Sirolimus/analogs & derivatives/pharmacology/therapeutic use
MH  - Synovial Membrane/drug effects/metabolism/pathology
MH  - TOR Serine-Threonine Kinases
MH  - Tumor Necrosis Factors/metabolism
EDAT- 2010/05/28 06:00
MHDA- 2010/09/04 06:00
CRDT- 2010/05/28 06:00
PHST- 2010/05/28 06:00 [entrez]
PHST- 2010/05/28 06:00 [pubmed]
PHST- 2010/09/04 06:00 [medline]
AID - 10.1002/art.27504 [doi]
PST - ppublish
SO  - Arthritis Rheum. 2010 Aug;62(8):2294-302. doi: 10.1002/art.27504.