Inhibition of systemic sclerosis dermal fibroblast type I collagen production and gene expression by simvastatin
Version of Record online: 30 MAR 2006
Copyright © 2006 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 54, Issue 4, pages 1298–1308, April 2006
How to Cite
Louneva, N., Huaman, G., Fertala, J. and Jiménez, S. A. (2006), Inhibition of systemic sclerosis dermal fibroblast type I collagen production and gene expression by simvastatin. Arthritis & Rheumatism, 54: 1298–1308. doi: 10.1002/art.21723
- Issue online: 30 MAR 2006
- Version of Record online: 30 MAR 2006
- Manuscript Accepted: 19 DEC 2005
- Manuscript Received: 26 AUG 2005
- NIH. Grant Number: AM-19616
To examine whether statins are capable of modulating collagen gene expression in cultured systemic sclerosis dermal fibroblasts.
Cultured dermal fibroblasts from 3 patients with diffuse systemic sclerosis of recent onset were treated with 5 μM and 10 μM of simvastatin for 3 or 4 days. Morphologic features, cytotoxicity, and type I collagen production and messenger RNA (mRNA) levels in the fibroblasts were examined. The effects of mevalonate, geranylgeranyl pyrophosphate (GGPP), and farnesyl pyrophosphate (FPP), which are lipids downstream from the hydroxymethylglutaryl–coenzyme A block, were also examined. Transient transfections with COL1A1 promoter-reporter constructs and electrophoretic gel mobility shift assays were utilized to examine COL1A1 transcription and Sp1 and CCAAT-box binding factor (CBF) binding.
Simvastatin did not cause morphologic changes or cytotoxicity in the fibroblasts, even after 4 days of treatment. Type I collagen production and mRNA levels showed a potent and dose-related inhibition following 3 and 4 days of treatment. The inhibition of collagen gene expression by simvastatin was completely reversed by mevalonate and GGPP, but not by FPP. The statin effects occurred at the transcriptional level and involved the proximal COL1A1 promoter region encompassing −174 bp. A significant reduction in Sp1 and CBF binding activity was also found in simvastatin-treated cells.
Simvastatin is a powerful inhibitor of type I collagen gene expression in normal and systemic sclerosis fibroblasts. The pleiotropic protective effects of statins on various endothelial and immune cell functions in conjunction with their potent inhibitory effects on type I collagen gene expression suggest that statins may be effective therapeutic agents in systemic sclerosis.