title: Fn14, a Downstream Target of the TGF-β Signaling Pathway, Regulates Fibroblast Activation.
abstract: Fibrosis, the hallmark of human injuries and diseases such as serious burns, is characterized by excessive collagen synthesis and myofibroblast accumulation. Transforming growth factor-β (TGF-β), a potent inducer of collagen synthesis, has been implicated in fibrosis in animals. In addition to TGF-β, fibroblast growth factor-inducible molecule 14 (Fn14) has been reported to play an important role in fibrotic diseases, such as cardiac fibrosis. However, the function and detailed regulatory mechanism of Fn14 in fibrosis are unclear. Here, we investigated the effect of Fn14 on the activation of human dermal fibroblasts. In normal dermal fibroblasts, TGF-β signaling increased collagen production and Fn14 expression. Furthermore, Fn14 siRNA blocked extracellular matrix gene expression; even when TGF-β signaling was activated by TGF-β1, fibroblast activation remained blocked in the presence of Fn14 siRNA. Overexpressing Fn14 increased extracellular matrix gene expression. In determining the molecular regulatory mechanism, we discovered that SMAD4, an important TGF-β signaling co-mediator, bound to the Fn14 promoter and activated Fn14 transcription. Taken together, these results indicate that the TGF-β signaling pathway activates Fn14 expression through the transcription factor SMAD4 and that activated Fn14 expression increases extracellular matrix synthesis and fibroblast activation. Therefore, Fn14 may represent a promising approach to preventing the excessive accumulation of collagen or ECM in skin fibrosis.
authors.affiliation: Medical Research Department of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
authors.forename: Shaoxian
authors.initials: S
authors.lastname: Chen
authors.affiliation: Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, China.
authors.forename: Juli
authors.initials: J
authors.lastname: Liu
authors.affiliation: Medical Research Department of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.|Pharmacy Department of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.affiliation: Burn and Wound Repair Surgery of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Lai
authors.affiliation: Pharmacy Department of General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong, China.
authors.forename: Litong
authors.initials: L
authors.lastname: Ye
authors.affiliation: Medical Research Department of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Medical Research Department of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
authors.forename: Xinghua
authors.initials: X
authors.lastname: Hou
authors.affiliation: Medical Research Department of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
authors.affiliation: Medical Research Department of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
authors.forename: Wenwei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Medical Research Department of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
authors.forename: Yueheng
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Medical Research Department of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Liu
authors.affiliation: Medical Research Department of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
authors.forename: Shufang
authors.initials: S
authors.lastname: Huang
authors.affiliation: Medical Research Department of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
authors.forename: Xiyong
authors.initials: X
authors.lastname: Yu
authors.affiliation: Medical Research Department of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
authors.forename: Dingzhang
authors.initials: D
authors.lastname: Xiao
mesh_terms: D000328:Adult; D003094:Collagen / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D012867:Skin / Q000166:cytology; D051901:Smad4 Protein / Q000378:metabolism; D000074050:TWEAK Receptor; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000502:physiology*; D055815:Young Adult
chemical_list: D018124:Receptors, Tumor Necrosis Factor; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; D016212:Transforming Growth Factor beta; D003094:Collagen