Linked Life Data

20517583

Source:http://linkedlifedata.com/resource/pubmed/id/20517583

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9-10
pubmed:dateCreated
2010-9-9
pubmed:abstractText
The invasive properties of fibroblast-like synoviocytes (FLS) correlate with radiographic and histologic damage in rheumatoid arthritis (RA) and pristane-induced arthritis (PIA). We previously determined that highly invasive FLS obtained from PIA-susceptible DA (blood type D, Agouti) rats have increased expression of genes associated with invasive cancers, including Villin-2/ezrin. Villin-2/ezrin mediates invasion via mTOR. In the present study we used the mTOR inhibitor rapamycin to assess the role of the ezrin-mTOR pathway on the invasive properties of FLS. FLS were isolated from synovial tissues from arthritic DA rats, and from RA patients. FLS were treated with rapamycin or dimethyl sulfoxide (DMSO) for 24 h and then studied in a Matrigel-invasion assay. Supernatants were assayed for matrix metalloproteinase (MMP) activity, and cell lysates were used for quantification of mTOR, p70S6K1, 4EBP1 and FAK, as well as their respective phosphorylated subsets. Actin filament and FAK localization were determined by immunofluorescence. Rapamycin decreased FLS invasion in DA and RA tissues by 93% and 82%, respectively. Rapamycin treatment reduced the phosphorylation of mTOR and its substrates, p70S6K1 and 4EBP1, confirming mTOR inhibition. In conclusion, rapamycin prevented actin reorganization in both DA and RA FLS, and inhibited the directional formation of lamellipodia. Phosphorylation of the lamellipodia marker FAK was also reduced by rapamycin. MMPs were not significantly affected by rapamycin. Rapamycin significantly reduced RA and DA rat FLS invasion via the suppression of the mTOR signaling pathway. This discovery suggests that rapamycin could have a role in RA therapy aimed at reducing the articular damage and erosive changes mediated by FLS.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
1528-3658
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
16
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
352-8
pubmed:meshHeading
pubmed:articleTitle
mTOR regulates the invasive properties of synovial fibroblasts in rheumatoid arthritis.
pubmed:affiliation
Laboratory of Experimental Rheumatology, Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural