Understanding fibrosis in systemic sclerosis: Shifting paradigms, emerging opportunities

Swati Bhattacharyya, Jun Wei, John Varga*

*Corresponding author for this work

Research output: Contribution to journalReview article

196 Citations (Scopus)

Abstract

Fibrosis in multiple organs is a prominent pathological finding and distinguishing hallmark of systemic sclerosis (SSc). Findings during the past 5 years have contributed to a more complete understanding of the complex cellular and molecular underpinning of fibrosis in SSc. Fibroblasts, the principal effector cells, are activated in the profibrotic cellular milieu by cytokines and growth factors, developmental pathways, endothelin 1 and thrombin. Innate immune signaling via Toll-like receptors, matrix-generated biomechanical stress signaling via integrins, hypoxia and oxidative stress seem to be implicated in perpetuating the process. Beyond chronic fibroblast activation, fibrosis represents a failure to terminate tissue repair, coupled with an expanded population of mesenchymal cells originating from bone marrow and transdifferentiation of epithelial cells, endothelial cells and pericytes. In addition, studies have identified intrinsic alterations in SSc fibroblasts resulting from epigenetic changes, as well as altered microRNA expression that might underlie the cell-autonomous, persistent activation phenotype of these cells. Precise characterization of the deregulated extracellular and intracellular signaling pathways, mediators and cellular differentiation programs that contribute to fibrosis in SSc will facilitate the development of selective, targeted therapeutic strategies. Effective antifibrotic therapy will ultimately involve novel compounds and repurposing of drugs that are already approved for other indications.

Original languageEnglish (US)
Pages (from-to)42-54
Number of pages13
JournalNature Reviews Rheumatology
Volume8
Issue number1
DOIs
StatePublished - Jan 1 2012

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Systemic Scleroderma
Fibrosis
Fibroblasts
Drug Repositioning
Pericytes
Toll-Like Receptors
Endothelin-1
MicroRNAs
Epigenomics
Integrins
Thrombin
Bone Marrow Cells
Intercellular Signaling Peptides and Proteins
Oxidative Stress
Endothelial Cells
Epithelial Cells
Cytokines
Phenotype
Therapeutics
Population

ASJC Scopus subject areas

  • Rheumatology

Cite this

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title = "Understanding fibrosis in systemic sclerosis: Shifting paradigms, emerging opportunities",
abstract = "Fibrosis in multiple organs is a prominent pathological finding and distinguishing hallmark of systemic sclerosis (SSc). Findings during the past 5 years have contributed to a more complete understanding of the complex cellular and molecular underpinning of fibrosis in SSc. Fibroblasts, the principal effector cells, are activated in the profibrotic cellular milieu by cytokines and growth factors, developmental pathways, endothelin 1 and thrombin. Innate immune signaling via Toll-like receptors, matrix-generated biomechanical stress signaling via integrins, hypoxia and oxidative stress seem to be implicated in perpetuating the process. Beyond chronic fibroblast activation, fibrosis represents a failure to terminate tissue repair, coupled with an expanded population of mesenchymal cells originating from bone marrow and transdifferentiation of epithelial cells, endothelial cells and pericytes. In addition, studies have identified intrinsic alterations in SSc fibroblasts resulting from epigenetic changes, as well as altered microRNA expression that might underlie the cell-autonomous, persistent activation phenotype of these cells. Precise characterization of the deregulated extracellular and intracellular signaling pathways, mediators and cellular differentiation programs that contribute to fibrosis in SSc will facilitate the development of selective, targeted therapeutic strategies. Effective antifibrotic therapy will ultimately involve novel compounds and repurposing of drugs that are already approved for other indications.",
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Understanding fibrosis in systemic sclerosis : Shifting paradigms, emerging opportunities. / Bhattacharyya, Swati; Wei, Jun; Varga, John.

In: Nature Reviews Rheumatology, Vol. 8, No. 1, 01.01.2012, p. 42-54.

Research output: Contribution to journalReview article

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