PMID- 24716596
OWN - NLM
STAT- MEDLINE
DCOM- 20150821
LR  - 20161020
IS  - 1439-7609 (Electronic)
IS  - 1439-7595 (Linking)
VI  - 25
IP  - 1
DP  - 2015 Jan
TI  - TNFalpha, PDGF, and TGFbeta synergistically induce synovial lining hyperplasia via 
      inducible PI3Kdelta.
PG  - 72-8
LID - 10.3109/14397595.2014.900847 [doi]
AB  - OBJECTIVES: To determine the mechanism underlying hypertrophic synovium in 
      rheumatoid arthritis (RA). METHODS: We examined micromass cultures of 
      fibroblast-like synoviocytes (FLSs) stimulated with tumor necrosis factor alpha 
      (TNFalpha), platelet-derived growth factor (PDGF), and/or transforming growth factor 
      beta (TGFbeta). The hypertrophic architecture of the micromasses, expression of 
      phosphoinositide 3 kinase (PI3K) isoforms, and persistent activation of PI3K-Akt 
      pathways were investigated. FLSs transfected with siRNA were also examined in the 
      micromass cultures. RESULTS: The combination of TNFalpha, PDGF, and TGFbeta (TPT 
      condition) induced obvious hypertrophic architecture of the intimal lining layer 
      in FLSs in micromass cultures, and was accompanied by upregulated expression of 
      matrix metalloproteinase-3 (MMP3), Cadherin-11, and PI3Kdelta. In monolayer FLSs, the 
      TPT condition enhanced the expression of PI3Kdelta and persistent activation of the 
      PI3K-Akt pathway. Knockdown of PI3Kdelta significantly inhibited the formation of the 
      hypertrophic synovial lining in the TPT condition. CONCLUSIONS: These results 
      collectively indicate that inducible PI3Kdelta plays a crucial role in persistent 
      activation of PI3K-Akt in FLSs, and in the formation of a hypertrophic synovial 
      lining. PI3Kdelta may be an alternative treatment target for the regulation of 
      proliferative synovium in RA.
FAU - Shibuya, Hideyuki
AU  - Shibuya H
AD  - Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine , 
      Kyoto , Japan.
FAU - Yoshitomi, Hiroyuki
AU  - Yoshitomi H
FAU - Murata, Koichi
AU  - Murata K
FAU - Kobayashi, Shio
AU  - Kobayashi S
FAU - Furu, Moritoshi
AU  - Furu M
FAU - Ishikawa, Masahiro
AU  - Ishikawa M
FAU - Fujii, Takayuki
AU  - Fujii T
FAU - Ito, Hiromu
AU  - Ito H
FAU - Matsuda, Shuichi
AU  - Matsuda S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140409
PL  - England
TA  - Mod Rheumatol
JT  - Modern rheumatology
JID - 100959226
RN  - 0 (Cadherins)
RN  - 0 (Platelet-Derived Growth Factor)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 156621-71-5 (osteoblast cadherin)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
SB  - IM
MH  - Arthritis, Rheumatoid/*metabolism/pathology
MH  - Cadherins/metabolism
MH  - Cells, Cultured
MH  - Humans
MH  - Hyperplasia/metabolism/pathology
MH  - Matrix Metalloproteinase 3/metabolism
MH  - Phosphatidylinositol 3-Kinase/*metabolism
MH  - Platelet-Derived Growth Factor/*pharmacology
MH  - RNA, Small Interfering
MH  - Signal Transduction/*drug effects/physiology
MH  - Synovial Membrane/drug effects/*metabolism/pathology
MH  - Transforming Growth Factor beta/*pharmacology
MH  - Tumor Necrosis Factor-alpha/*pharmacology
MH  - Up-Regulation/drug effects
OTO - NOTNLM
OT  - Fibroblast-like synoviocytes
OT  - PDGF
OT  - PI3K/Akt pathway
OT  - PI3Kdelta
OT  - TGFbeta
EDAT- 2014/04/11 06:00
MHDA- 2015/08/22 06:00
CRDT- 2014/04/11 06:00
PHST- 2014/04/11 06:00 [entrez]
PHST- 2014/04/11 06:00 [pubmed]
PHST- 2015/08/22 06:00 [medline]
AID - 10.3109/14397595.2014.900847 [doi]
PST - ppublish
SO  - Mod Rheumatol. 2015 Jan;25(1):72-8. doi: 10.3109/14397595.2014.900847. Epub 2014 
      Apr 9.