Amelioration of collagen-induced arthritis in rats by adenovirus-mediated PTEN gene transfer

Chrong-Reen Wang, Ai-Li Shiau, Shih Yao Chen, Ling Ling Lin, Ming Hong Tai, Gia Shing Shieh, Pey Ru Lin, Yi Te Yo, Che Hsin Lee, Shiao Mei Kuo, Ming-Fei Liu, I. Ming Jou, Chyun-Yu Yang, Po Chuan Shen, Hwei Ling Lee, Chao-Liang Wu

Research output: Contribution to journalArticle

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Abstract

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 β-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-1β. Furthermore, PTEN gene transfer led to down-regulation of Akt activation and increased apoptosis in the ankle joints. Conclusion. 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.

Original languageEnglish
Pages (from-to)1650-1656
Number of pages7
JournalArthritis and Rheumatism
Volume58
Issue number6
DOIs
Publication statusPublished - 2008 Jun 1

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Experimental Arthritis
Adenoviridae
Phosphatidylinositol 3-Kinase
Vascular Endothelial Growth Factor A
Genes
Rheumatoid Arthritis
Ankle Joint
Microvessels
Therapeutics
Galactosidases
Chromosomes, Human, Pair 10
Interleukin-1
Chemokines
Phosphoric Monoester Hydrolases
Ankle
Radiography
Arthritis
Histology
Anti-Inflammatory Agents
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

Cite this

Wang, Chrong-Reen ; Shiau, Ai-Li ; Chen, Shih Yao ; Lin, Ling Ling ; Tai, Ming Hong ; Shieh, Gia Shing ; Lin, Pey Ru ; Yo, Yi Te ; Lee, Che Hsin ; Kuo, Shiao Mei ; Liu, Ming-Fei ; Jou, I. Ming ; Yang, Chyun-Yu ; Shen, Po Chuan ; Lee, Hwei Ling ; Wu, Chao-Liang. / Amelioration of collagen-induced arthritis in rats by adenovirus-mediated PTEN gene transfer. In: Arthritis and Rheumatism. 2008 ; Vol. 58, No. 6. pp. 1650-1656.
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title = "Amelioration of collagen-induced arthritis in rats by adenovirus-mediated PTEN gene transfer",
abstract = "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 β-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-1β. Furthermore, PTEN gene transfer led to down-regulation of Akt activation and increased apoptosis in the ankle joints. Conclusion. 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.",
author = "Chrong-Reen Wang and Ai-Li Shiau and Chen, {Shih Yao} and Lin, {Ling Ling} and Tai, {Ming Hong} and Shieh, {Gia Shing} and Lin, {Pey Ru} and Yo, {Yi Te} and Lee, {Che Hsin} and Kuo, {Shiao Mei} and Ming-Fei Liu and Jou, {I. Ming} and Chyun-Yu Yang and Shen, {Po Chuan} and Lee, {Hwei Ling} and Chao-Liang Wu",
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Wang, C-R, Shiau, A-L, Chen, SY, Lin, LL, Tai, MH, Shieh, GS, Lin, PR, Yo, YT, Lee, CH, Kuo, SM, Liu, M-F, Jou, IM, Yang, C-Y, Shen, PC, Lee, HL & Wu, C-L 2008, 'Amelioration of collagen-induced arthritis in rats by adenovirus-mediated PTEN gene transfer', Arthritis and Rheumatism, vol. 58, no. 6, pp. 1650-1656. https://doi.org/10.1002/art.23517

Amelioration of collagen-induced arthritis in rats by adenovirus-mediated PTEN gene transfer. / Wang, Chrong-Reen; Shiau, Ai-Li; Chen, Shih Yao; Lin, Ling Ling; Tai, Ming Hong; Shieh, Gia Shing; Lin, Pey Ru; Yo, Yi Te; Lee, Che Hsin; Kuo, Shiao Mei; Liu, Ming-Fei; Jou, I. Ming; Yang, Chyun-Yu; Shen, Po Chuan; Lee, Hwei Ling; Wu, Chao-Liang.

In: Arthritis and Rheumatism, Vol. 58, No. 6, 01.06.2008, p. 1650-1656.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Amelioration of collagen-induced arthritis in rats by adenovirus-mediated PTEN gene transfer

AU - Wang, Chrong-Reen

AU - Shiau, Ai-Li

AU - Chen, Shih Yao

AU - Lin, Ling Ling

AU - Tai, Ming Hong

AU - Shieh, Gia Shing

AU - Lin, Pey Ru

AU - Yo, Yi Te

AU - Lee, Che Hsin

AU - Kuo, Shiao Mei

AU - Liu, Ming-Fei

AU - Jou, I. Ming

AU - Yang, Chyun-Yu

AU - Shen, Po Chuan

AU - Lee, Hwei Ling

AU - Wu, Chao-Liang

PY - 2008/6/1

Y1 - 2008/6/1

N2 - 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 β-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-1β. Furthermore, PTEN gene transfer led to down-regulation of Akt activation and increased apoptosis in the ankle joints. Conclusion. 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.

AB - 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 β-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-1β. Furthermore, PTEN gene transfer led to down-regulation of Akt activation and increased apoptosis in the ankle joints. Conclusion. 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.

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