Peroxisome proliferator-activated receptor γ: Innate protection from excessive fibrogenesis and potential therapeutic target in systemic sclerosis

Jun Wei, Swati Bhattacharyya, John Varga*

*Corresponding author for this work

Research output: Contribution to journalReview article

49 Citations (Scopus)

Abstract

Purpose of Review: Progressive organ fibrosis and pulmonary arterial hypertension (PAH) are the leading causes of death in patients with systemic sclerosis (SSc). However, the pathogenesis and the link between these two processes remain obscure. A better understanding of these events is needed in order to facilitate the discovery and development of effective therapies for SSc. Recent Findings: Recent reports provide evidence that the orphan receptor peroxisome proliferator-activated receptor γ (PPARγ), better known for its pivotal role in metabolism, has potent effects on inflammation, fibrogenesis and vascular remodeling and is important in the pathogenesis of fibrosis and PAH, and as a potential therapeutic target in SSc. The studies discussed in this review indicate that ligands of PPARγ potently modulate connective tissue turnover and suggest that aberrant expression or function of PPARγ is associated with, and very likely contributes to, the progression of pathological fibrosis and vascular remodeling. These observations are of particularly relevance because FDA-approved drugs of the thiazolidinedione class currently used for the treatment of obesity-associated type 2 diabetes activate PPARγ signaling. Moreover, novel PPARγ ligands with selective activity are under development or in clinical trials for inflammatory diseases, asthma, Alzheimer disease and cancer. Summary: Drugs targeting the PPARγ pathway might be effective for the control of fibrosis as well as pathological vascular remodeling underlying PAH and, therefore, might have a therapeutic potential in SSc. A greater understanding of the mechanisms underlying the antifibrogenic and vascular remodeling activities of PPARγ ligands will be necessary in order to advance these drugs into clinical use.

Original languageEnglish (US)
Pages (from-to)671-676
Number of pages6
JournalCurrent Opinion in Rheumatology
Volume22
Issue number6
DOIs
StatePublished - Nov 1 2010

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Peroxisome Proliferator-Activated Receptors
Systemic Scleroderma
Fibrosis
Pulmonary Hypertension
Ligands
Therapeutics
Drug Delivery Systems
Pharmaceutical Preparations
Connective Tissue
Type 2 Diabetes Mellitus
Cause of Death
Alzheimer Disease
Asthma
Obesity
Clinical Trials
Inflammation
Vascular Remodeling

Keywords

  • fibroblast
  • fibrosis
  • fibrosis therapy
  • myofibroblast
  • peroxisome proliferator-activated receptor g
  • pulmonary arterial hypertension
  • scleroderma
  • transforming growth factor β

ASJC Scopus subject areas

  • Rheumatology

Cite this

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title = "Peroxisome proliferator-activated receptor γ: Innate protection from excessive fibrogenesis and potential therapeutic target in systemic sclerosis",
abstract = "Purpose of Review: Progressive organ fibrosis and pulmonary arterial hypertension (PAH) are the leading causes of death in patients with systemic sclerosis (SSc). However, the pathogenesis and the link between these two processes remain obscure. A better understanding of these events is needed in order to facilitate the discovery and development of effective therapies for SSc. Recent Findings: Recent reports provide evidence that the orphan receptor peroxisome proliferator-activated receptor γ (PPARγ), better known for its pivotal role in metabolism, has potent effects on inflammation, fibrogenesis and vascular remodeling and is important in the pathogenesis of fibrosis and PAH, and as a potential therapeutic target in SSc. The studies discussed in this review indicate that ligands of PPARγ potently modulate connective tissue turnover and suggest that aberrant expression or function of PPARγ is associated with, and very likely contributes to, the progression of pathological fibrosis and vascular remodeling. These observations are of particularly relevance because FDA-approved drugs of the thiazolidinedione class currently used for the treatment of obesity-associated type 2 diabetes activate PPARγ signaling. Moreover, novel PPARγ ligands with selective activity are under development or in clinical trials for inflammatory diseases, asthma, Alzheimer disease and cancer. Summary: Drugs targeting the PPARγ pathway might be effective for the control of fibrosis as well as pathological vascular remodeling underlying PAH and, therefore, might have a therapeutic potential in SSc. A greater understanding of the mechanisms underlying the antifibrogenic and vascular remodeling activities of PPARγ ligands will be necessary in order to advance these drugs into clinical use.",
keywords = "fibroblast, fibrosis, fibrosis therapy, myofibroblast, peroxisome proliferator-activated receptor g, pulmonary arterial hypertension, scleroderma, transforming growth factor β",
author = "Jun Wei and Swati Bhattacharyya and John Varga",
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T2 - Innate protection from excessive fibrogenesis and potential therapeutic target in systemic sclerosis

AU - Wei, Jun

AU - Bhattacharyya, Swati

AU - Varga, John

PY - 2010/11/1

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N2 - Purpose of Review: Progressive organ fibrosis and pulmonary arterial hypertension (PAH) are the leading causes of death in patients with systemic sclerosis (SSc). However, the pathogenesis and the link between these two processes remain obscure. A better understanding of these events is needed in order to facilitate the discovery and development of effective therapies for SSc. Recent Findings: Recent reports provide evidence that the orphan receptor peroxisome proliferator-activated receptor γ (PPARγ), better known for its pivotal role in metabolism, has potent effects on inflammation, fibrogenesis and vascular remodeling and is important in the pathogenesis of fibrosis and PAH, and as a potential therapeutic target in SSc. The studies discussed in this review indicate that ligands of PPARγ potently modulate connective tissue turnover and suggest that aberrant expression or function of PPARγ is associated with, and very likely contributes to, the progression of pathological fibrosis and vascular remodeling. These observations are of particularly relevance because FDA-approved drugs of the thiazolidinedione class currently used for the treatment of obesity-associated type 2 diabetes activate PPARγ signaling. Moreover, novel PPARγ ligands with selective activity are under development or in clinical trials for inflammatory diseases, asthma, Alzheimer disease and cancer. Summary: Drugs targeting the PPARγ pathway might be effective for the control of fibrosis as well as pathological vascular remodeling underlying PAH and, therefore, might have a therapeutic potential in SSc. A greater understanding of the mechanisms underlying the antifibrogenic and vascular remodeling activities of PPARγ ligands will be necessary in order to advance these drugs into clinical use.

AB - Purpose of Review: Progressive organ fibrosis and pulmonary arterial hypertension (PAH) are the leading causes of death in patients with systemic sclerosis (SSc). However, the pathogenesis and the link between these two processes remain obscure. A better understanding of these events is needed in order to facilitate the discovery and development of effective therapies for SSc. Recent Findings: Recent reports provide evidence that the orphan receptor peroxisome proliferator-activated receptor γ (PPARγ), better known for its pivotal role in metabolism, has potent effects on inflammation, fibrogenesis and vascular remodeling and is important in the pathogenesis of fibrosis and PAH, and as a potential therapeutic target in SSc. The studies discussed in this review indicate that ligands of PPARγ potently modulate connective tissue turnover and suggest that aberrant expression or function of PPARγ is associated with, and very likely contributes to, the progression of pathological fibrosis and vascular remodeling. These observations are of particularly relevance because FDA-approved drugs of the thiazolidinedione class currently used for the treatment of obesity-associated type 2 diabetes activate PPARγ signaling. Moreover, novel PPARγ ligands with selective activity are under development or in clinical trials for inflammatory diseases, asthma, Alzheimer disease and cancer. Summary: Drugs targeting the PPARγ pathway might be effective for the control of fibrosis as well as pathological vascular remodeling underlying PAH and, therefore, might have a therapeutic potential in SSc. A greater understanding of the mechanisms underlying the antifibrogenic and vascular remodeling activities of PPARγ ligands will be necessary in order to advance these drugs into clinical use.

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KW - fibrosis

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KW - peroxisome proliferator-activated receptor g

KW - pulmonary arterial hypertension

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KW - transforming growth factor β

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