TNFα, PDGF, and TGFβ synergistically induce synovial lining hyperplasia via inducible PI3Kδ.
OBJECTIVE
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 α (TNFα), platelet-derived growth factor (PDGF), and/or transforming growth factor β (TGFβ). 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 TNFα, PDGF, and TGFβ (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 PI3Kδ. In monolayer FLSs, the TPT condition enhanced the expression of PI3Kδ and persistent activation of the PI3K-Akt pathway. Knockdown of PI3Kδ significantly inhibited the formation of the hypertrophic synovial lining in the TPT condition.


CONCLUSIONS
These results collectively indicate that inducible PI3Kδ plays a crucial role in persistent activation of PI3K-Akt in FLSs, and in the formation of a hypertrophic synovial lining. PI3Kδ may be an alternative treatment target for the regulation of proliferative synovium in RA.
Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine , Kyoto , Japan.
Hideyuki
H
Shibuya
Hiroyuki
H
Yoshitomi
Koichi
K
Murata
Shio
S
Kobayashi
Moritoshi
M
Furu
Masahiro
M
Ishikawa
Takayuki
T
Fujii
Hiromu
H
Ito
Shuichi
S
Matsuda
D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D015820:Cadherins; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C086960:osteoblast cadherin; D058539:Phosphatidylinositol 3-Kinase; D019278:Matrix Metalloproteinase 3
Fibroblast-like synoviocytes; PDGF; PI3K/Akt pathway; PI3Kδ; TGFβ