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J Invest Dermatol. 2018 Jan;138(1):78-88. doi: 10.1016/j.jid.2017.08.024. Epub 2017 Sep 1.

Therapeutic Targeting of TAZ and YAP by Dimethyl Fumarate in Systemic Sclerosis Fibrosis.

Author information

1
Arthritis Center, Boston University School of Medicine, Boston, Massachusetts, USA.
2
Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA.
3
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, USA.
4
Arthritis Center, Boston University School of Medicine, Boston, Massachusetts, USA. Electronic address: trojanme@bu.edu.

Abstract

Systemic sclerosis (scleroderma, SSc) is a devastating fibrotic disease with few treatment options. Fumaric acid esters, including dimethyl fumarate (DMF, Tecfidera; Biogen, Cambridge, MA), have shown therapeutic effects in several disease models, prompting us to determine whether DMF is effective as a treatment for SSc dermal fibrosis. We found that DMF blocks the profibrotic effects of transforming growth factor-β (TGFβ) in SSc skin fibroblasts. Mechanistically, we found that DMF treatment reduced nuclear localization of transcriptional coactivator with PDZ binding motif (TAZ) and Yes-associated protein (YAP) proteins via inhibition of the phosphatidylinositol 3 kinase/protein kinase B (Akt) pathway. In addition, DMF abrogated TGFβ/Akt1 mediated inhibitory phosphorylation of glycogen kinase 3β (GSK3β) and a subsequent β-transducin repeat-containing proteins (βTRCP) mediated proteasomal degradation of TAZ, as well as a corresponding decrease of TAZ/YAP transcriptional targets. Depletion of TAZ/YAP recapitulated the antifibrotic effects of DMF. We also confirmed the increase of TAZ/YAP in skin biopsies from patients with diffuse SSc. We further showed that DMF significantly diminished nuclear TAZ/YAP localization in fibroblasts cultured on a stiff surface. Importantly, DMF prevented bleomycin-induced skin fibrosis in mice. Together, our work demonstrates a mechanism of the antifibrotic effect of DMF via inhibition of Akt1/GSK3β/TAZ/YAP signaling and confirms a critical role of TAZ/YAP in mediating the profibrotic responses in dermal fibroblasts. This study supports the use of DMF as a treatment for SSc dermal fibrosis.

PMID:
28870693
PMCID:
PMC5742036
DOI:
10.1016/j.jid.2017.08.024
[Indexed for MEDLINE]
Free PMC Article

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