PGC-1α regulates autophagy to promote fibroblast activation and tissue fibrosis

Zhang Y, Shen L, Zhu H, Dreissigacker K, Distler D, Zhou X, Györfi AH, Bergmann C, Meng X, Dees C, Trinh-Minh T, Ludolph I, Horch RE, Ramming A, Schett G, Distler J (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Annals of the Rheumatic Diseases BMJ Publishing Group

Book Volume: 79

Pages Range: 1227-1233

Journal Issue: 9

DOI: 10.1136/annrheumdis-2020-216963

Abstract

Objectives 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). Methods 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. Results 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. Conclusion 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.

Authors with CRIS profile

Yun Zhang Department of Medicine 3 – Rheumatology and Immunology Lichong Shen Professur für Molekulare Mechanismen der Organfibrose Andrea-Hermina Györfi Department of Medicine 3 – Rheumatology and Immunology Xianyi Meng Juniorprofessur für Osteoimmunologie Clara Dees Department of Medicine 3 – Rheumatology and Immunology Ingo Ludolph Department of Plastic and Hand Surgery Raymund Horch Professur für Plastische Chirurgie und Handchirurgie Andreas Ramming Medizinische Fakultät Georg Schett Lehrstuhl für Innere Medizin III Jörg Distler Professur für Molekulare Mechanismen der Organfibrose

How to cite

APA:

Zhang, Y., Shen, L., Zhu, H., Dreissigacker, K., Distler, D., Zhou, X.,... Distler, J. (2020). PGC-1α regulates autophagy to promote fibroblast activation and tissue fibrosis. Annals of the Rheumatic Diseases, 79(9), 1227-1233. https://doi.org/10.1136/annrheumdis-2020-216963

MLA:

Zhang, Yun, et al. "PGC-1α regulates autophagy to promote fibroblast activation and tissue fibrosis." Annals of the Rheumatic Diseases 79.9 (2020): 1227-1233.

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