Heparan sulfate-dependent ERK activation contributes to the overexpression of fibrotic proteins and enhanced contraction by scleroderma fibroblasts

被引：37

作者：

Chen, Yunliang ^{[2
]}

Leask, Andrew ^{[3
]}

Abraham, David J.

Pala, Daphne ^{[3
]}

Xu Shiwen

Khan, Korsa

Liu, Shangxi ^{[3
]}

Carter, David E. ^{[4
]}

Wilcox-Adelman, Sarah ^{[5
,6
]}

Goetinck, Paul ^{[5
,6
]}

Denton, Christopher P.

Black, Carol M.

Pitsillides, Andrew A. ^{[7
]}

Sarraf, Catherine E. ^{[1
]}

Eastwood, Mark ^{[1
]}

机构：

[1] Univ Westminster, Sch Biosci, London W1W 6UW, England

[2] UCL, London WC1E 6BT, England

[3] Univ Western Ontario, Schulich Sch Dent, London, ON N6A 3K7, Canada

[4] London Reg Genom Ctr, London, ON, Canada

[5] Harvard Univ, Sch Med, Boston, MA 02115 USA

[6] Massachusetts Gen Hosp, Boston, MA 02114 USA

[7] Univ London Royal Vet Coll, London NW1 0TU, England

来源：

ARTHRITIS AND RHEUMATISM | 2008年 / 58卷 / 02期

关键词：

D O I：

10.1002/art.23146

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective. To investigate the contribution of heparan sulfate proteoglycan and Ras/MEK/ERK to the overexpression of profibrotic proteins and the enhanced contractile ability of dermal fibroblasts from patients with systemic sclerosis (SSc; scleroderma). Methods. The effects of the MEK/ERK inhibitor U0126, the heparan sulfate side chain formation inhibitor beta-xyloside, and soluble heparin on the overexpression of profibrotic genes were compared in fibroblasts from lesional skin of patients with diffuse SSc and fibroblasts from healthy control subjects. Identified protein expressions were compared with the contractile abilities of fibroblasts while they resided within a collagen lattice. Forces generated were measured using a culture force monitor. Results. Inhibiting MEK/ERK with U0126 significantly reduced expression of a cohort of proadhesive and procontractile proteins that normally are overexpressed by scleroderma fibroblasts, including integrin alpha 4 and integrin beta 1. Antagonizing heparan sulfate side chain formation with beta-xyloside or the addition of soluble heparin prevented ERK activation, in addition to reducing the expression of these proadhesive/contractile proteins. Treatment with either U0126, beta-xyloside, or heparin resulted in a reduction in the overall peak contractile force generated by dermal fibroblasts. Blocking platelet-derived growth factor receptor with Gleevec (imatinib mesylate) reduced overall contractile ability and the elevated syndecan 4 expression and ERK activation in SSc fibroblasts. Conclusion. The results of this study suggest that heparan sulfate-dependent ERK activation contributes to the enhanced contractile ability demonstrated by dermal fibroblasts from lesional skin of patients with scleroderma. These results are consistent with the notion that the MEK/ERK procontractile pathway is dysregulated in scleroderma dermal fibroblasts. Additionally, the results suggest that antagonizing the MEK/ERK pathway is likely to modulate heparan sulfate proteoglycan activity, which in turn may have a profound effect on the fibrotic response in SSc.

引用

页码：577 / 585

页数：9

共 45 条

[1] Tumor necrosis factor α suppresses the induction of connective tissue growth factor by transforming growth factor-β in normal and scleroderma fibroblasts [J].