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2017 ; 114
(18
): 4757-4762
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Unifying mechanism for different fibrotic diseases
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Wernig G
; Chen SY
; Cui L
; Van Neste C
; Tsai JM
; Kambham N
; Vogel H
; Natkunam Y
; Gilliland DG
; Nolan G
; Weissman IL
Proc Natl Acad Sci U S A
2017[May]; 114
(18
): 4757-4762
PMID28424250
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Fibrotic diseases are not well-understood. They represent a number of different
diseases that are characterized by the development of severe organ fibrosis
without any obvious cause, such as the devastating diseases idiopathic pulmonary
fibrosis (IPF) and scleroderma. These diseases have a poor prognosis comparable
with endstage cancer and are uncurable. Given the phenotypic differences, it was
assumed that the different fibrotic diseases also have different pathomechanisms.
Here, we demonstrate that many endstage fibrotic diseases, including IPF;
scleroderma; myelofibrosis; kidney-, pancreas-, and heart-fibrosis; and
nonalcoholic steatohepatosis converge in the activation of the AP1 transcription
factor c-JUN in the pathologic fibroblasts. Expression of the related AP1
transcription factor FRA2 was restricted to pulmonary artery hypertension.
Induction of c-Jun in mice was sufficient to induce severe fibrosis in multiple
organs and steatohepatosis, which was dependent on sustained c-Jun expression.
Single cell mass cytometry revealed that c-Jun activates multiple signaling
pathways in mice, including pAkt and CD47, which were also induced in human
disease. ?CD47 antibody treatment and VEGF or PI3K inhibition reversed various
organ c-Jun-mediated fibroses in vivo. These data suggest that c-JUN is a central
molecular mediator of most fibrotic conditions.
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