Inhibitory Effects of PPARγ Ligands on TGF-β1–Induced Corneal Myofibroblast Transformation

Jeon, Kye-Im; Kulkarni, Ajit A.; Woeller, Collynn F.; Phipps, Richard P.; Sime, Patricia J.; Hindman, Holly B.; Huxlin, Krystel R.

doi:10.1016/j.ajpath.2014.01.026

Cited by 56 publications

(85 citation statements)

References 43 publications

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“…Other anti-fibrotic factors that are relevant in the eye are PPAR-γ ligands that were shown to suppress corneal myofibroblasts (Jeon et al, 2014), cell culture hypoxia that inhibits TGF-β-induced keratocyte-to-myofibroblast activation (Xing and Bonanno, 2009), similar to dermal myofibroblasts (Modarressi et al, 2010), and possibly insulin-like growth factor (IGF) that activates keratocytes to produce ECM but with a quality that resembles the normal stroma in the cornea rather than fibrotic scar (Berthaut et al, 2011;Etheredge et al, 2010).…”

Section: Interleukin (Il)-1mentioning

confidence: 99%

Myofibroblasts

Hinz¹

2016

Experimental Eye Research

351

341

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Myofibroblasts are activated in response to tissue injury with the primary task to repair lost or damaged extracellular matrix. Enhanced collagen secretion and subsequent contraction - scarring - are part of the normal wound healing response and crucial to restore tissue integrity. Due to myofibroblasts ability to repair but not regenerate, accumulation of scar tissue is always associated with reduced organ performance. This is a fair price to pay by the body for not falling apart. Whereas myofibroblasts typically vanish after successful repair, dysregulation of the normal repair process can lead to persistent myofibroblast activation, for instance by chronic inflammation or mechanical stress in the tissue. Excessive repair leads to the accumulation of stiff collagenous ECM contractures - fibrosis - with dramatic consequences for organ function. The clinical need to terminate detrimental myofibroblast activities has stimulated researchers to answer a number of essential questions: where do myofibroblasts come from, what are the factors leading to their activation, how do we discriminate myofibroblasts from other cells, what is the molecular basis for their contractile activity, and how can we stop or at least control them? This article reviews the current state of the myofibroblast literature by emphasizing their role in ocular repair and fibrosis. It appears that although the eye is quite an extraordinary organ, ocular myofibroblasts behave or misbehave just like their siblings in other organs.

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Section: Interleukin (Il)-1mentioning

confidence: 99%

Myofibroblasts

Hinz¹

2016

Experimental Eye Research

351

341

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“…A solution would be a drug that selectively targets the TGF-β cascade, but with minimal side-effects. Our group and others have shown several ligands of PPARγ to be effective corneal anti-fibrotics in vitro (Jeon et al 2014, Kuriyan et al 2012, Pan et al 2009, Pan et al 2011) and in vivo (Huxlin et al 2013, Jeon et al 2014). PPARγ is a transcription factor belonging to a nuclear receptor superfamily that regulates important cellular functions, including metabolism, adipogenesis, proliferation, differentiation and inflammatory responses (Simpson-Haidaris et al 2010).…”

Section: Introductionmentioning

confidence: 84%

Inhibitory effects of PPARγ ligands on TGF-β1-induced CTGF expression in cat corneal fibroblasts

Jeon

Phipps

Sime

et al. 2015

Experimental Eye Research

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Ligands of Peroxisome Proliferator Activated Receptor gamma (PPARγ) possess strong anti-fibrotic properties in the cornea and several other body tissues. In the cornea, we recently showed this class of molecules to prevent stromal myofibroblast differentiation partially by blocking the actions of p38 mitogen-activated protein kinase (MAPK). However, given the important role assigned to connective tissue growth factor (CTGF) in mediating corneal fibrosis, here we asked whether PPARγ ligands also act by affecting transforming growth factor-β (TGF-β 1-induced expression of CTGF in cultured corneal fibroblasts. Corneal keratocytes were isolated from young, adult cats and early passage cells were exposed to TGF-β1 with or without the PPARγ ligands Rosiglitazone, Troglitazone and 15d-PGJ2. Western blots were used to assay levels of CTGF and alpha smooth muscle actin (αSMA), a marker of myofibroblast differentiation. CTGF siRNA demonstrated a critical role for CTGF in TGF-β1-mediated myofibroblast differentiation, while exogenously applied CTGF potentiated the pro-fibrogenic effects of TGF-β1. TGF-β1-mediated increases in CTGF and αSMA expression were strongly inhibited by all three PPARγ ligands tested, and by a c-jun N-terminal kinase (JNK) inhibitor. However, while extracellular signal-regulated kinase (ERK) 1/2, protein kinase B (AKT) and p38 MAPK inhibitors also blocked TGF-β1-induced αSMA induction, they did not dampen TGF-β1-induced increases in levels of CTGF. Thus, we conclude that PPARγ ligands block TGF-β-induced increases in CTGF levels in cat corneal fibroblasts. They appear to do this in addition to their anti-fibrotic effect on p38 MAPK, providing a second intracellular pathway by which PPARγ ligands block αSMA induction.

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“…PPARγ induces protection from excessive fibrogenesis [117]. In the eye, PPARγ ligands (15-deoxy-delta12,14-prostaglandin J2, troglitazone, and rosiglitazone) have been shown to suppress corneal myofibroblasts [120].…”

Section: Interplays Among the Above Regulatorsmentioning

confidence: 99%

The Myofibroblast: TGFβ-1, A Conductor which Plays a Key Role in Fibrosis by Regulating the Balance between PPARγ and the Canonical WNT Pathway

Lecarpentier¹,

Schussler

Claes

et al. 2017

Nuclear Receptor Research

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Abstract. Myofibroblasts are non-muscular contractile cells that occur physiologically in organs such as in stem villi of the human placenta during normal pregnancies. They have the ability to contract and relax in response to changes in the volume of the intervillous chamber. Myofibroblasts are also found in many pathological states, and are involved in wound healing and fibrosis processes in several organs such as liver, lung, kidney, and heart. During fibrosis, the contractile phenomenon is a relaxation-free mechanism, associated with the synthesis of collagen in the extracellular matrix (ECM), which leads to irreversible fibrosis, tissue retraction and finally apoptosis of the myofibroblasts. The molecular motor of myofibroblasts is the non-muscle myosin type II (NMII). Differentiation of fibroblasts into myofibroblast is largely regulated by the Transforming Growth Factor-β1 (TGF-β1). This system regulates the canonical WNT/β-catenin pathway in a positive manner and PPARγ in a negative manner. WNT/β-catenin promotes fibrosis while PPARγ prevents fibrosis. This review focuses on the contractile properties of myofibroblasts and on the TGF-β1 conductor which regulates the antagonism between PPARγ and the canonical WNT/β-catenin pathway.

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Inhibitory Effects of PPARγ Ligands on TGF-β1–Induced Corneal Myofibroblast Transformation

Cited by 56 publications

References 43 publications

Myofibroblasts

Myofibroblasts

Inhibitory effects of PPARγ ligands on TGF-β1-induced CTGF expression in cat corneal fibroblasts

The Myofibroblast: TGFβ-1, A Conductor which Plays a Key Role in Fibrosis by Regulating the Balance between PPARγ and the Canonical WNT Pathway

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