Anti-fibrotic action of pirfenidone in Dupuytren’s disease-derived fibroblasts View Full Text


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Article Info

DATE

2016-11-11

AUTHORS

Chaoming Zhou, Fang Liu, Phillip H. Gallo, Mark E. Baratz, Sandeep Kathju, Latha Satish

ABSTRACT

BackgroundDupuytren’s disease (DD) is a complex fibro-proliferative disorder of the hand that is often progressive and eventually can cause contractures of the affected fingers. Transforming growth factor beta (TGF-β1) has been implicated as a key stimulator of myofibroblast activity and fascial contraction in DD. Pirfenidone (PFD) is an active small molecule shown to inhibit TGF-β1-mediated action in other fibrotic disorders. This study investigates the efficacy of PFD in vitro in inhibiting TGF-β1-mediated cellular functions leading to Dupuytren’s fibrosis.MethodsFibroblasts harvested from (DD) and carpal tunnel (CT)- tissues were treated with or without TGF-β1 and/or PFD and were subjected to cell migration, cell proliferation and cell contraction assays. ELISA; western blots and real time RT-PCR assays were performed to determine the levels of fibronectin; p-Smad2/Smad3; alpha-smooth muscle actin (α-SMA), α2 chain of type I collagen and α1 chain of type III collagen respectively.ResultsOur results show that PFD effectively inhibits TGF-β1-induced cell migration, proliferation and cell contractile properties of both CT- and DD-derived fibroblasts. TGF-β1−induced α-SMA mRNA and protein levels were inhibited at the higher concentration of PFD (800 μg/ml). Interestingly, TGF-β1 induction of type I and type III collagens and fibronectin was inhibited by PFD in both CT- and DD- derived fibroblasts, but the effect was more prominent in DD cells. PFD down-regulated TGF-β1-induced phosphorylation of Smad2/Smad3, a key factor in the TGF-β1 signaling pathway.ConclusionTaken together these results suggest the PFD can potentially prevent TGF-β1−induced fibroblast to myofibroblast transformation and inhibit ECM production mainly Type I- and Type III- collagen and fibronectin in DD-derived fibroblasts. Further in-vivo studies with PFD may lead to a novel therapeutic application in preventing the progression or recurrence of Dupuytren’s disease. More... »

PAGES

469

References to SciGraph publications

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  • 2014-12-23. Pirfenidone gel in patients with localized scleroderma: a phase II study in ARTHRITIS RESEARCH & THERAPY
  • 2013-01-06. Increased CCT-eta expression is a marker of latent and active disease and a modulator of fibroblast contractility in Dupuytren’s contracture in CELL STRESS AND CHAPERONES
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        "description": "BackgroundDupuytren\u2019s disease (DD) is a complex fibro-proliferative disorder of the hand that is often progressive and eventually can cause contractures of the affected fingers. Transforming growth factor beta (TGF-\u03b21) has been implicated as a key stimulator of myofibroblast activity and fascial contraction in DD. Pirfenidone (PFD) is an active small molecule shown to inhibit TGF-\u03b21-mediated action in other fibrotic disorders. This study investigates the efficacy of PFD in vitro in inhibiting TGF-\u03b21-mediated cellular functions leading to Dupuytren\u2019s fibrosis.MethodsFibroblasts harvested from (DD) and carpal tunnel (CT)- tissues were treated with or without TGF-\u03b21 and/or PFD and were subjected to cell migration, cell proliferation and cell contraction assays. ELISA; western blots and real time RT-PCR assays were performed to determine the levels of fibronectin; p-Smad2/Smad3; alpha-smooth muscle actin (\u03b1-SMA), \u03b12 chain of type I collagen and \u03b11 chain of type III collagen respectively.ResultsOur results show that PFD effectively inhibits TGF-\u03b21-induced cell migration, proliferation and cell contractile properties of both CT- and DD-derived fibroblasts. TGF-\u03b21\u2212induced \u03b1-SMA mRNA and protein levels were inhibited at the higher concentration of PFD (800\u00a0\u03bcg/ml). Interestingly, TGF-\u03b21 induction of type I and type III collagens and fibronectin was inhibited by PFD in both CT- and DD- derived fibroblasts, but the effect was more prominent in DD cells. PFD down-regulated TGF-\u03b21-induced phosphorylation of Smad2/Smad3, a key factor in the TGF-\u03b21 signaling pathway.ConclusionTaken together these results suggest the PFD can potentially prevent TGF-\u03b21\u2212induced fibroblast to myofibroblast transformation and inhibit ECM production mainly Type I- and Type III- collagen and fibronectin in DD-derived fibroblasts. Further in-vivo studies with PFD may lead to a novel therapeutic application in preventing the progression or recurrence of Dupuytren\u2019s disease.", 
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    34 schema:description BackgroundDupuytren’s disease (DD) is a complex fibro-proliferative disorder of the hand that is often progressive and eventually can cause contractures of the affected fingers. Transforming growth factor beta (TGF-β1) has been implicated as a key stimulator of myofibroblast activity and fascial contraction in DD. Pirfenidone (PFD) is an active small molecule shown to inhibit TGF-β1-mediated action in other fibrotic disorders. This study investigates the efficacy of PFD in vitro in inhibiting TGF-β1-mediated cellular functions leading to Dupuytren’s fibrosis.MethodsFibroblasts harvested from (DD) and carpal tunnel (CT)- tissues were treated with or without TGF-β1 and/or PFD and were subjected to cell migration, cell proliferation and cell contraction assays. ELISA; western blots and real time RT-PCR assays were performed to determine the levels of fibronectin; p-Smad2/Smad3; alpha-smooth muscle actin (α-SMA), α2 chain of type I collagen and α1 chain of type III collagen respectively.ResultsOur results show that PFD effectively inhibits TGF-β1-induced cell migration, proliferation and cell contractile properties of both CT- and DD-derived fibroblasts. TGF-β1−induced α-SMA mRNA and protein levels were inhibited at the higher concentration of PFD (800 μg/ml). Interestingly, TGF-β1 induction of type I and type III collagens and fibronectin was inhibited by PFD in both CT- and DD- derived fibroblasts, but the effect was more prominent in DD cells. PFD down-regulated TGF-β1-induced phosphorylation of Smad2/Smad3, a key factor in the TGF-β1 signaling pathway.ConclusionTaken together these results suggest the PFD can potentially prevent TGF-β1−induced fibroblast to myofibroblast transformation and inhibit ECM production mainly Type I- and Type III- collagen and fibronectin in DD-derived fibroblasts. Further in-vivo studies with PFD may lead to a novel therapeutic application in preventing the progression or recurrence of Dupuytren’s disease.
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    41 schema:keywords CT
    42 ConclusionTaken
    43 DD
    44 DD cells
    45 Dupuytren's disease
    46 ECM production
    47 I collagen
    48 MethodsFibroblasts
    49 RT-PCR assays
    50 ResultsOur results
    51 Smad2/Smad3
    52 Smad3
    53 TGF
    54 TGF-β1
    55 TGF-β1 induction
    56 Western blot
    57 actin
    58 action
    59 active small molecules
    60 activity
    61 alpha-smooth muscle actin
    62 anti-fibrotic actions
    63 applications
    64 assays
    65 beta
    66 blot
    67 carpal tunnel
    68 cell migration
    69 cell proliferation
    70 cells
    71 cellular functions
    72 chain
    73 collagen
    74 concentration
    75 contractile properties
    76 contraction
    77 contraction assays
    78 contracture
    79 disease
    80 disorders
    81 effect
    82 efficacy
    83 efficacy of pirfenidone
    84 factor beta
    85 factors
    86 fibro-proliferative disorder
    87 fibroblasts
    88 fibronectin
    89 fibrosis
    90 fibrotic disorders
    91 finger
    92 function
    93 growth factor beta
    94 hand
    95 high concentrations
    96 induction
    97 key factors
    98 key stimulator
    99 levels
    100 levels of fibronectin
    101 mRNA
    102 migration
    103 molecules
    104 muscle actin
    105 myofibroblast activity
    106 myofibroblast transformation
    107 novel therapeutic applications
    108 pathway
    109 phosphorylation
    110 pirfenidone
    111 production
    112 progression
    113 proliferation
    114 properties
    115 protein levels
    116 real-time RT-PCR assays
    117 recurrence
    118 results
    119 small molecules
    120 stimulator
    121 study
    122 therapeutic applications
    123 time RT-PCR assay
    124 tissue
    125 transformation
    126 tunnel
    127 type I
    128 type I collagen
    129 type III collagen
    130 types
    131 vivo studies
    132 α-SMA mRNA
    133 α1 chain
    134 α2 chain
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