FK506 inhibits the enhancing effects of transforming growth factor (TGF)-β1 on collagen expression and TGF-β/Smad signalling in keloid fibroblasts: implication for new therapeutic approach

Cs, Wu; Wu, Peng; Ah, Fang; Chen, Lan

doi:10.1111/j.1365-2133.2012.11023.x

Cited by 57 publications

(42 citation statements)

References 48 publications

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“…Interestingly, immunosuppressive peptidyl-prolyl isomerase inhibitors like FK506 have been ascribed potent antifibrotic effects in lung fibrosis (40)(41)(42)(43). FK506 suppresses collagen synthesis and expression of the TGF-b 1 receptor in dermal and lung fibroblasts, but the underlying mechanisms are largely unclear (41,44,45). Our findings put forward the possibility that inhibition of FKBP10 might contribute to the antifibrotic effects of FK506.…”

Section: Discussionmentioning

confidence: 78%

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

Staab-Weijnitz

Fernandez

Knüppel

et al. 2015

Am J Respir Crit Care Med

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Rationale: Increased abundance and stiffness of the extracellular matrix, in particular collagens, is a hallmark of idiopathic pulmonary fibrosis (IPF). FK506-binding protein 10 (FKBP10) is a collagen chaperone, mutations of which have been indicated in the reduction of extracellular matrix stiffness (e.g., in osteogenesis imperfecta).Objectives: To assess the expression and function of FKBP10 in IPF. Methods:We assessed FKBP10 expression in bleomycininduced lung fibrosis (using quantitative reverse transcriptase-polymerase chain reaction, Western blot, and immunofluorescence), analyzed microarray data from 99 patients with IPF and 43 control subjects from a U.S. cohort, and performed Western blot analysis from 6 patients with IPF and 5 control subjects from a German cohort. Subcellular localization of FKBP10 was assessed by immunofluorescent stainings. The expression and function of FKBP10, as well as its regulation by endoplasmic reticulum stress or transforming growth factor-b 1 , was analyzed by small interfering RNA-mediated loss-of-function experiments, quantitative reverse transcriptase-polymerase chain reaction, Western blot, and quantification of secreted collagens in the lung and in primary human lung fibroblasts (phLF). Effects on collagen secretion were compared with those of the drugs nintedanib and pirfenidone, recently approved for IPF.Measurements and Main Results: FKBP10 expression was up-regulated in bleomycin-induced lung fibrosis and IPF. Immunofluorescent stainings demonstrated localization to interstitial (myo)fibroblasts and CD68 1 macrophages. Transforming growth factor-b 1 , but not endoplasmic reticulum stress, induced FKBP10 expression in phLF. The small interfering RNA-mediated knockdown of FKBP10 attenuated expression of profibrotic mediators and effectors, including collagens I and V and a-smooth muscle actin, on the transcript and protein level. Importantly, loss of FKBP10 expression significantly suppressed collagen secretion by phLF.Conclusions: FKBP10 might be a novel drug target for IPF.

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Section: Discussionmentioning

confidence: 78%

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

Staab-Weijnitz

Fernandez

Knüppel

et al. 2015

Am J Respir Crit Care Med

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“…Of these articles on cellular biology, one that deserves to be mentioned is that of Wu et al (21). Concerning the behavior of keloid fibroblasts activated with tissue growth factors (TGF-β1), this study concluded that tacrolimus inhibits the growth factor action on the fibroblast in vitro.…”

Section: Discussionmentioning

confidence: 90%

Qualitative analysis of the deposit of collagen in bladder suture of rats treated with tacrolimus combined with mycophenolate-mofetil

2014

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ARTICLE INFO ______________________________________________________________ ______________________Purpose: To evaluate the synthesis of type I (mature) and type III (immature) collagen in bladder suture of rats treated with a combination of tacrolimus and mycophenolate mofetil for 15 days. Materials and Methods:Thirty rats were divided into 3 groups: the sham, control and experimental groups. All the animals underwent laparotomy, cystotomy and bladder suture in two planes with surgical PDS 5-0 thread. The sham group did not receive treatment. The control group received saline solution, and the experimental group received 0.1mg/kg/day of tacrolimus with 20mg/kg/day of mycophenolate mofetil, for 15 days. From then on, the tacrolimus was dosed. The surgical specimens of the bladder suture area were processed so that the total type I and type III collagen could be measured by the picrosirius red technique.Results: There was a predominance of type I collagen production in the sham and control groups compared to the experimental group, in which type III collagen was predominant. The production of total collagen did not change. Conclusion:The association of tacrolimus and mycophenolate mofetil in animals qualitatively changes the production of collagen after 15 days with a predominance of type III collagen.

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“…Poza modulowaniem ekspresji TGF-β tamoksyfen wpływa również na ekspresję IGF, VEGF i bFGF [15]. Indukowaną TGF-β1 proliferację fibroblastów keloidowych oraz syntezę kolagenu hamują również retinoidy, genisteina i takrolimus [19,80]. Innymi kierunkami modulowania ekspresji TGF-β1 w procesie gojenia ran są: śródskórna iniekcja ludzkiego rekombinowanego TGF-β3 (avotermin) -izoformy TGF-β o działaniu antyfibrotycznymoraz terapie genowe wykorzystujące antysensowe oligonukleotydy TGF-β1 i przeciwciała dla TGF-β1 [81][82][83].…”

Section: Metody Leczenia Keloidówunclassified

Review papers Some molecular aspects of the fibroproliferative process in keloids

Antończak¹,

Jurzak²,

Adamczyk³

et al. 2015

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StreSzczenieProcesy naprawcze (reperatywne) uszkodzonych tkanek należą do podstawowych procesów biologicznych zapewniających utrzymanie homeostazy organizmu. Zasadniczo obejmują fazę zapalną, proliferacyjną oraz przebudowy. Końcowym efektem gojenia się uszkodzonych tkanek jest powstanie blizny. Nieprawidłowości w przebiegu gojenia się ran mogą być przyczyną tworzenia keloidów (bliznowców). W patofizjologii keloidów obserwuje się zarówno nieprawidłowości w migracji, proliferacji i apoptozie komórek, jak i w syntezie oraz sekrecji białek, cytokin, enzymów proteolitycznych degradujących składniki macierzy pozakomórkowej, a także ich inhibitorów. Dotychczasowo stosowane terapie nie przynoszą zadowalających efektów kosmetycznych. Obecnie prowadzone badania skupiają się na poszukiwaniu metod bezpośredniego hamowania procesu fibroproliferacyjnego poprzez modulowanie ekspresji cytokin, hamowanie proliferacji fibroblastów oraz regulowanie biosyntezy i degradacji składników macierzy pozakomórkowej. AbStrActReparation of damaged tissues is an essential biological process that ensures maintenance of homeostasis. Basically it includes phases of inflammation, proliferation and remodeling. The result of healing of damaged tissues is scar formation. Abnormalities in the course of wound healing may lead to keloid formation. The pathophysiology of keloids is characterized by improper migration, proliferation and apoptosis of cells as well as imbalanced synthesis and secretion of proteins, cytokines, proteolytic enzymes and their inhibitors. To date, applied therapeutic methods do not lead to satisfactory cosmetic results of the treatment. Current research focuses on developing methods for direct inhibition of the fibroproliferative process, mainly through modulation of cytokine expression and in consequence suppression of fibroblast proliferation and balancing of synthesis and degradation of extracellular matrix components.

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FK506 inhibits the enhancing effects of transforming growth factor (TGF)-β1 on collagen expression and TGF-β/Smad signalling in keloid fibroblasts: implication for new therapeutic approach

Abstract: Our results demonstrate that FK506 effectively blocks the TGF-β/Smad signalling pathway in KFs by downregulation of TGF-β receptors and suggest that FK506 may be included in the armamentarium for treating keloids.

Cited by 57 publications

References 48 publications

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

Qualitative analysis of the deposit of collagen in bladder suture of rats treated with tacrolimus combined with mycophenolate-mofetil

Review papers Some molecular aspects of the fibroproliferative process in keloids

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