A potential contribution of altered cathepsin L expression to the development of dermal fibrosis and vasculopathy in systemic sclerosis

2016 ◽  
Vol 25 (4) ◽  
pp. 287-292 ◽  
Author(s):  
Takashi Yamashita ◽  
Yoshihide Asano ◽  
Takashi Taniguchi ◽  
Kouki Nakamura ◽  
Ryosuke Saigusa ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Cathepsin L ◽  
Potential Contribution ◽  
Dermal Fibrosis

Therapeutic effect of cyclin‐dependent kinase 4/6 inhibitor on dermal fibrosis in murine models of systemic sclerosis

2021 ◽  
Author(s):  
Akio Yamamoto ◽  
Tetsuya Saito ◽  
Tadashi Hosoya ◽  
Kimito Kawahata ◽  
Yoshihide Asano ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Therapeutic Effect ◽  
Cyclin Dependent Kinase ◽  
Murine Models ◽  
Dermal Fibrosis

scholarly journals Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis

2019 ◽  
Vol 11 (497) ◽  
pp. eaaw0790 ◽  
Author(s):  
Joseph Yusup Shin ◽  
James Daniel Beckett ◽  
Rustam Bagirzadeh ◽  
Tyler J. Creamer ◽  
Ami A. Shah ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Transcriptome Profiling ◽  
Chromatin Accessibility ◽  
Epigenetic Mechanism ◽  
Enhancer Activity ◽  
Dermal Fibrosis ◽  
Transforming Growth Factor Β2 ◽  
Skin Explants

In systemic sclerosis (SSc), previously healthy adults develop an inflammatory prodrome with subsequent progressive fibrosis of the skin and viscera. SSc has a weak signature for genetic contribution, and there are few pathogenic insights or targeted treatments for this condition. Here, chromatin accessibility and transcriptome profiling coupled with targeted epigenetic editing revealed constitutive activation of a previously unannotated transforming growth factor–β2 (TGFB2) enhancer maintained through epigenetic memory in SSc. The resulting autocrine TGFβ2 signaling enforced a profibrotic synthetic state in ex vivo fibroblasts from patients with SSc. Inhibition of NF-κB or BRD4 achieved sustained inhibition of TGFB2 enhancer activity, mitigated profibrotic gene expression, and reversed dermal fibrosis in patient skin explants. These findings suggest a potential epigenetic mechanism of fibrosis in SSc and inform a regulatory mechanism of TGFB2, a major profibrotic cytokine.

A potential contribution of decreased galectin‐7 expression in stratified epithelia to the development of cutaneous and oesophageal manifestations in systemic sclerosis

2019 ◽  
Vol 28 (5) ◽  
pp. 536-542 ◽  
Author(s):  
Ryosuke Saigusa ◽  
Takashi Yamashita ◽  
Shunsuke Miura ◽  
Megumi Hirabayashi ◽  
Kouki Nakamura ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Potential Contribution ◽  
Stratified Epithelia

scholarly journals Allogeneic marrow transplantation in patients with severe systemic sclerosis: Resolution of dermal fibrosis

2006 ◽  
Vol 54 (6) ◽  
pp. 1982-1986 ◽  
Author(s):  
Richard A. Nash ◽  
Peter A. McSweeney ◽  
J. Lee Nelson ◽  
Mark Wener ◽  
George E. Georges ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Marrow Transplantation ◽  
Dermal Fibrosis ◽  
Allogeneic Marrow Transplantation ◽  
Allogeneic Marrow

scholarly journals Failed Degradation of JunB Contributes to Overproduction of Type I Collagen and Development of Dermal Fibrosis in Patients With Systemic Sclerosis

2014 ◽  
Vol 67 (1) ◽  
pp. 243-253 ◽  
Author(s):  
Markella Ponticos ◽  
Ioannis Papaioannou ◽  
Shiwen Xu ◽  
Alan M. Holmes ◽  
Korsa Khan ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Type I Collagen ◽  
Type I ◽  
Dermal Fibrosis

Experimental models of dermal fibrosis and systemic sclerosis

2013 ◽  
Vol 80 (1) ◽  
pp. 23-28 ◽  
Author(s):  
Jérôme Avouac ◽  
Muriel Elhai ◽  
Yannick Allanore
Keyword(s):  
Systemic Sclerosis ◽  
Experimental Models ◽  
Dermal Fibrosis

scholarly journals Decreased cathepsin V expression due to Fli1 deficiency contributes to the development of dermal fibrosis and proliferative vasculopathy in systemic sclerosis

Rheumatology ◽  
2013 ◽  
Vol 52 (5) ◽  
pp. 790-799 ◽  
Author(s):  
S. Noda ◽  
Y. Asano ◽  
T. Takahashi ◽  
K. Akamata ◽  
N. Aozasa ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Dermal Fibrosis ◽  
Cathepsin V

scholarly journals Interferon regulatory factor 7 (IRF7) represents a link between inflammation and fibrosis in the pathogenesis of systemic sclerosis

2019 ◽  
Vol 78 (11) ◽  
pp. 1583-1591 ◽  
Author(s):  
Minghua Wu ◽  
Brian Skaug ◽  
Xiongjie Bi ◽  
Tingting Mills ◽  
Gloria Salazar ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Interferon Regulatory Factor ◽  
Dermal Fibroblasts ◽  
Type I ◽  
Type I Ifn ◽  
Hydroxyproline Content ◽  
Regulatory Factor ◽  
Dermal Fibrosis ◽  
Interferon Regulatory Factor 7

ObjectivesThere is considerable evidence that implicates dysregulation of type I interferon signalling (or type I IFN signature) in the pathogenesis of systemic sclerosis (SSc). Interferon regulatory factor 7 (IRF7) has been recognised as a master regulator of type I IFN signalling. The objective of this study was to elucidate the role of IRF7 in dermal fibrosis and SSc pathogenesis.MethodsSSc and healthy control skin biopsies were investigated to determine IRF7 expression and activation. The role of IRF7 in fibrosis was investigated using IRF7 knockout (KO) mice in the bleomycin-induced and TSK/+mouse models. In vitro experiments with dermal fibroblasts from patients with SSc and healthy controls were performed.ResultsIRF7 expression was significantly upregulated and activated in SSc skin tissue and explanted SSc dermal fibroblasts compared with unaffected, matched controls. Moreover, IRF7 expression was stimulated by IFN-α in dermal fibroblasts. Importantly, IRF7 co-immunoprecipitated with Smad3, a key mediator of transforming growth factor (TGF)-β signalling, and IRF7 knockdown reduced profibrotic factors in SSc fibroblasts. IRF7 KO mice demonstrated attenuated dermal fibrosis and inflammation compared with wild-type mice in response to bleomycin. Specifically, hydroxyproline content, dermal thickness as well as Col1a2, ACTA2 and interleukin-6 mRNA levels were significantly attenuated in IRF7 KO mice skin tissue. Furthermore, IRF7 KO in TSK/+mice attenuated hydroxyproline content, subcutaneous hypodermal thickness, Col1a2 mRNA as well as α-smooth muscle actin and fibronectin expression.ConclusionsIRF7 is upregulated in SSc skin, interacts with Smad3 and potentiates TGF-β-mediated fibrosis, and therefore may represent a promising therapeutic target in SSc.

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