PGC-1α regulates autophagy to promote fibroblast activation and tissue fibrosis.
Animals
Autophagy
/ genetics
Bleomycin
/ pharmacology
Blotting, Western
Collagen
/ biosynthesis
Disease Models, Animal
Fibroblasts
/ physiology
Fibrosis
Fluorescent Antibody Technique
Humans
Mice
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
/ physiology
Polymerase Chain Reaction
Receptor, Transforming Growth Factor-beta Type I
/ metabolism
Scleroderma, Systemic
/ genetics
Signal Transduction
/ drug effects
Transforming Growth Factor beta
/ metabolism
Up-Regulation
fibroblasts
systemic sclerosis
treatment
Journal
Annals of the rheumatic diseases
ISSN: 1468-2060
Titre abrégé: Ann Rheum Dis
Pays: England
ID NLM: 0372355
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
13
01
2020
revised:
23
04
2020
accepted:
16
05
2020
pubmed:
3
6
2020
medline:
2
10
2020
entrez:
3
6
2020
Statut:
ppublish
Résumé
Coactivators are a heterogeneous family of transcriptional regulators that are essential for modulation of transcriptional outcomes and fine-tune numerous cellular processes. The aim of the present study was to evaluate the role of the coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in the pathogenesis of systemic sclerosis (SSc). Expression of PGC-1α was analysed by real-time PCR, western blot and immunofluorescence. Modulation of autophagy was analysed by reporter studies by expression of autophagy-related genes. The effects of PGC-1α knockdown on collagen production and myofibroblast differentiation were analysed in cultured human fibroblasts and in two mouse models with fibroblast-specific knockout of PGC-1α. The expression of PGC-1α was induced in dermal fibroblasts of patients with SSc and experimental murine fibrosis. Transforming growth factor beta (TGFβ), hypoxia and epigenetic mechanisms regulate the expression of PGC-1α in fibroblasts. Knockdown of PGC-1α prevented the activation of autophagy by TGFβ and this translated into reduced fibroblast-to-myofibroblast differentiation and collagen release. Knockout of PGC-1α in fibroblasts prevented skin fibrosis induced by bleomycin and by overexpression of a constitutively active TGFβ receptor type I. Moreover, pharmacological inhibition of PGC-1α by SR18292 induced regression of pre-established, bleomycin-induced skin fibrosis. PGC-1α is upregulated in SSc and promotes autophagy to foster TGFβ-induced fibroblast activation. Targeting of PGC-1α prevents aberrant autophagy, inhibits fibroblast activation and tissue fibrosis and may over therapeutic potential.
Identifiants
pubmed: 32482644
pii: annrheumdis-2020-216963
doi: 10.1136/annrheumdis-2020-216963
doi:
Substances chimiques
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
0
Transforming Growth Factor beta
0
Bleomycin
11056-06-7
Collagen
9007-34-5
Receptor, Transforming Growth Factor-beta Type I
EC 2.7.11.30
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1227-1233Informations de copyright
© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: JHWD has consultancy relationships with Actelion, Active Biotech, Anamar, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB. JHWD has received research funding from Anamar, Active Biotech, Array Biopharma, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB. JHWD is stock owner of 4D Science.