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Dr. Naff has received consulting fees from Fairway Medical Technologies (less than $10,000).
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Systemic Sclerosis
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Selective expression of connective tissue growth factor in fibroblasts in vivo promotes systemic tissue fibrosis
Article first published online: 8 MAR 2010
DOI: 10.1002/art.27382
Copyright © 2010 by the American College of Rheumatology
Additional Information
How to Cite
Sonnylal, S., Shi-Wen, X., Leoni, P., Naff, K., Van Pelt, C. S., Nakamura, H., Leask, A., Abraham, D., Bou-Gharios, G. and de Crombrugghe, B. (2010), Selective expression of connective tissue growth factor in fibroblasts in vivo promotes systemic tissue fibrosis. Arthritis & Rheumatism, 62: 1523–1532. doi: 10.1002/art.27382
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Dr. Naff has received consulting fees from Fairway Medical Technologies (less than $10,000).
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Dr. Leask is a New Investigator of the Arthritis Society (Scleroderma Society of Ontario), recipient of an Early Researcher Award from the Ontario Ministry of Research and Innovation, and a member of the Canadian Scleroderma Research Group New Emerging Team.
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Dr. Leask owns stock in FibroGen.
Publication History
- Issue published online: 29 APR 2010
- Article first published online: 8 MAR 2010
- Accepted manuscript online: 8 MAR 2010 12:00AM EST
- Manuscript Accepted: 28 JAN 2010
- Manuscript Received: 20 OCT 2009
Funded by
- NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases, Center of Research Translation). Grant Number: 1-P50-AR-054144
- Arthritis Research Campaign, UK
- Welton Foundation
- National Cancer Institute Cancer Center Core. Grant Number: CA-16672-29
- Canadian Institute of Health Research
- Ontario Thoracic Society
Abstract
Objective
Connective tissue growth factor (CTGF) is a cysteine-rich secreted matricellular protein involved in wound healing and tissue repair. Enhanced and prolonged expression of CTGF has been associated with tissue fibrosis in humans. However, questions remain as to whether CTGF expression alone is sufficient to drive fibrosis. This study was undertaken to investigate whether CTGF alone is sufficient to cause fibrosis in intact animals and whether its effects are mediated through activation of transforming growth factor β (TGFβ) signaling or through distinct signal transduction pathways.
Methods
We generated mice overexpressing CTGF in fibroblasts under the control of the fibroblast-specific collagen α2(I) promoter enhancer. Tissues such as skin, lung, and kidney were harvested for histologic analysis. Mouse embryonic fibroblasts were prepared from embryos (14.5 days postcoitum) for biochemical analysis.
Results
Mice overexpressing CTGF in fibroblasts were susceptible to accelerated tissue fibrosis affecting the skin, lung, kidney, and vasculature, most notably the small arteries. We identified a marked expansion of the myofibroblast cell population in the dermis. RNA analysis of transgenic dermal fibroblasts revealed elevated expression of key matrix genes, consistent with a fibrogenic response. CTGF induced phosphorylation of p38, ERK-1/2, JNK, and Akt, but not Smad3, in transgenic mouse fibroblasts compared with wild-type mouse fibroblasts. Transfection experiments showed significantly increased basal activity of the CTGF and serum response element promoters, and enhanced induction of the CTGF promoter in the presence of TGFβ.
Conclusion
These results demonstrate that selective expression of CTGF in fibroblasts alone causes tissue fibrosis in vivo through specific signaling pathways, integrating cues from the extracellular matrix into signal transduction pathways to orchestrate pivotal biologic responses relevant to tissue repair and fibrosis.