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Published on: February 15, 2019
Targeting the TGFbeta, endothelin-1 and CCN2 axis to combat fibrosis in scleroderma
1CIHR Group in Skeletal Development and Remodeling, Division of Oral Biology, Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada N6A 5C1. Andrew.Leask@schulich.uwo.ca
Abstract:
Fibrosis affects organs such as the skin, liver, kidney and lung and is a cause of significant morbidity. There is no therapy for fibrosis. Recent significant molecular insights into the signaling underlying the fibrosis in the autoimmune connective tissue disease scleroderma (systemic sclerosis, SSc) have been made. Transforming growth factor beta (TGFbeta) signaling is a major contributor to fibrogenesis, including in SSc. However, it is now appreciated that TGFbeta-dependent and TGFbeta-independent mechanisms play key roles in the pathological fibrosis in SSc. In particular the potent pro-fibrotic proteins endothelin-1 (ET-1) and CCN2 (connective tissue growth factor, CTGF) are believed to play an essential role in this process. This review summarizes these recent crucial observations.
Insights
Fibrosis, a condition affecting multiple organs, currently lacks effective therapies. Recent research highlights both transforming growth factor beta (TGFbeta)-dependent and independent pathways, involving endothelin-1 (ET-1) and CCN2, in systemic sclerosis (SSc) fibrosis.
Area of Science:
- Fibrosis research
- Molecular mechanisms of fibrogenesis
- Autoimmune connective tissue diseases
Background:
- Fibrosis is a significant cause of morbidity affecting organs like skin, liver, kidney, and lung.
- Current therapeutic options for fibrosis are limited.
- Systemic sclerosis (SSc) is an autoimmune disease characterized by pathological fibrosis.
Purpose of the Study:
- To review recent molecular insights into fibrogenesis in systemic sclerosis (SSc).
- To highlight the roles of transforming growth factor beta (TGFbeta) signaling in fibrosis.
- To discuss TGFbeta-dependent and independent mechanisms in SSc fibrosis.
Main Methods:
- Literature review of recent molecular findings in SSc fibrosis.
- Focus on key pro-fibrotic signaling pathways.
- Analysis of the roles of specific fibrotic proteins.
Main Results:
- Transforming growth factor beta (TGFbeta) signaling is a major driver of fibrogenesis.
- Both TGFbeta-dependent and TGFbeta-independent pathways contribute to SSc fibrosis.
- Endothelin-1 (ET-1) and CCN2 (connective tissue growth factor, CTGF) are identified as crucial pro-fibrotic proteins.
Conclusions:
- Understanding the molecular underpinnings of fibrosis is critical for developing therapies.
- Targeting both TGFbeta-dependent and independent pathways may be necessary for treating SSc fibrosis.
- Endothelin-1 and CCN2 represent important therapeutic targets in fibrotic diseases.
