Document Detail


Protein tyrosine phosphatase expression profile of rheumatoid arthritis fibroblast-like synoviocytes: a novel role of SH2 domain-containing phosphatase 2 as a modulator of invasion and survival.
MedLine Citation:
PMID:  23335101     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: The fibroblast-like synoviocytes (FLS) in the synovial intimal lining of the joint are key mediators of inflammation and joint destruction in rheumatoid arthritis (RA). In RA, these cells aggressively invade the extracellular matrix, producing cartilage-degrading proteases and inflammatory cytokines. The behavior of FLS is controlled by multiple interconnected signal transduction pathways involving reversible phosphorylation of proteins on tyrosine residues. However, little is known about the role of the protein tyrosine phosphatases (PTPs) in FLS function. This study was undertaken to explore the expression of all of the PTP genes (the PTPome) in FLS.
METHODS: A comparative screening of the expression of the PTPome in FLS from patients with RA and patients with osteoarthritis (OA) was conducted. The functional effect on RA FLS of SH2 domain-containing phosphatase 2 (SHP-2), a PTP that was up-regulated in RA, was then analyzed by knockdown using cell-permeable antisense oligonucleotides.
RESULTS: PTPN11 was overexpressed in RA FLS compared to OA FLS. Knockdown of PTPN11, which encodes SHP-2, reduced the invasion, migration, adhesion, spreading, and survival of RA FLS. Additionally, signaling in response to growth factors and inflammatory cytokines was impaired by SHP-2 knockdown. RA FLS that were deficient in SHP-2 exhibited decreased activation of focal adhesion kinase and mitogen-activated protein kinases.
CONCLUSION: These findings indicate that SHP-2 has a novel role in mediating human FLS function and suggest that it promotes the invasiveness and survival of RA FLS. Further investigation may reveal SHP-2 to be a candidate therapeutic target for RA.
Authors:
Stephanie M Stanford; Michael F Maestre; Amanda M Campbell; Beatrix Bartok; William B Kiosses; David L Boyle; Heather A Arnett; Tomas Mustelin; Gary S Firestein; Nunzio Bottini
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  65     ISSN:  1529-0131     ISO Abbreviation:  Arthritis Rheum.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-24     Completed Date:  2013-06-18     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1171-80     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2013 by the American College of Rheumatology.
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MeSH Terms
Descriptor/Qualifier:
Arthritis, Rheumatoid / enzymology*,  genetics
Cell Line
Cell Movement
Fibroblasts / enzymology*,  pathology
Gene Expression Regulation, Enzymologic
Gene Knockdown Techniques
Humans
Oligonucleotides, Antisense / pharmacology
Osteoarthritis / enzymology*,  genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics,  metabolism*
Protein Tyrosine Phosphatases / genetics,  metabolism*
Signal Transduction
Synovial Membrane / enzymology*,  pathology
Up-Regulation
Grant Support
ID/Acronym/Agency:
AR-478255/AR/NIAMS NIH HHS; R01 AI070555/AI/NIAID NIH HHS; R01 AR047825/AR/NIAMS NIH HHS; UL1 TR000100/TR/NCATS NIH HHS; UL1-TR-000100/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/Oligonucleotides, Antisense; EC 3.1.3.48/PTPN11 protein, human; EC 3.1.3.48/Protein Tyrosine Phosphatase, Non-Receptor Type 11; EC 3.1.3.48/Protein Tyrosine Phosphatases
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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