Amelioration of collagen-induced arthritis in rats by adenovirus-mediated PTEN gene transfer.
OBJECTIVE
The phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway is known to be activated in rheumatoid arthritis (RA) synovial tissue, which impacts cell growth, proliferation, survival, and migration. Phosphatase and tensin homolog deleted from chromosome 10 (PTEN) functions as a negative regulator of PI 3-kinase signaling, thus blocking Akt activation. The aim of this study was to examine the effect of PTEN gene transfer in rats with collagen-induced arthritis (CIA).


METHODS
Adenoviral vectors encoding human PTEN (AdPTEN) or beta-galactosidase (AdLacZ) were injected intraarticularly into rats with CIA, and their treatment responses were monitored by measures of clinical, radiographic, and histologic changes. The expression of phosphorylated Akt, total Akt, vascular endothelial growth factor (VEGF), proinflammatory cytokines, and chemokines, as well as the extent of microvessel density in the ankle joints were determined.


RESULTS
AdPTEN treatment reduced Akt phosphorylation and decreased VEGF production in human RA synovial fibroblasts. Compared with AdLacZ treatment of the rats with CIA, AdPTEN treatment significantly reduced ankle circumference, articular index scores, radiography scores, and histology scores, and also decreased microvessel density and levels of VEGF and interleukin-1beta. Furthermore, PTEN gene transfer led to down-regulation of Akt activation and increased apoptosis in the ankle joints.


CONCLUSIONS
This study is the first to demonstrate the in vivo effect of intraarticular gene delivery of PTEN on amelioration of arthritis symptoms in rats with CIA, which involved antiangiogenic, antiproliferative, and antiinflammatory effects of PTEN via inhibition of the PI 3-kinase/Akt signaling pathway. Our findings also implicate the PI 3-kinase/Akt pathway as a therapeutic target for the treatment of RA or other inflammatory diseases.
Wang
Chrong-Reen
CR
National Cheng Kung University Medical College, Tainan, Taiwan.
Shiau
Ai-Li
AL
Chen
Shih-Yao
SY
Lin
Ling-Ling
LL
Tai
Ming-Hong
MH
Shieh
Gia-Shing
GS
Lin
Pey-Ru
PR
Yo
Yi-Te
YT
Lee
Che-Hsin
CH
Kuo
Shiao-Mei
SM
Liu
Ming-Fei
MF
Jou
I-Ming
IM
Yang
Chyun-Yu
CY
Shen
Po-Chuan
PC
Lee
Hwei-Ling
HL
Wu
Chao-Liang
CL
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000843:Ankle Joint / Q000473:pathology; D001169:Arthritis, Experimental / Q000473:pathology / Q000628:therapy*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism*; D022761:Gene Transfer, Horizontal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human