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PGC-1α regulates autophagy to promote fibroblast activation and tissue fibrosis
  1. Yun Zhang1,
  2. Lichong Shen1,
  3. Honglin Zhu1,2,
  4. Katja Dreissigacker1,
  5. Diana Distler1,
  6. Xiang Zhou1,
  7. Andrea Hermina Györfi1,
  8. Christina Bergmann1,
  9. Xianyi Meng1,
  10. Clara Dees1,
  11. Thuong Trinh-Minh1,
  12. Ingo Ludolph3,
  13. Raymund Horch3,
  14. Andreas Ramming1,
  15. Georg Schett1,
  16. Jörg H W Distler1
  1. 1 Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Erlangen, Germany
  2. 2 Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan, PR China
  3. 3 Department of Plastic and Hand Surgery and Laboratory for Tissue Engineering and Regenerative Medicine, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), University Hospital of Erlangen, Erlangen, Germany
  1. Correspondence to Dr Jörg H W Distler, Department of Internal Medicine III, University of Erlangen, Erlangen 91054, Germany; joerg.distler{at}


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.

  • fibroblasts
  • systemic sclerosis
  • treatment

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  • Handling editor Josef S Smolen

  • Contributors YZ and JHWD designed the study. YZ, LS, HZ, KD, DD, HG, CB, XZ, XM, CD and TT were involved in acquisition of data. YZ, CB, AR, GS and JHWD were involved in interpretation of data. YZ and JHWD were involved in manuscript preparation. IL and RH provided essential samples.

  • Funding Grants DI 1537/9-1 and 1537/9-2, DI 1537/11-1, DI 1537/12-1, DI 1537/13-1, DI 1537/14-1 and RA 2506/3-1 of the German Research Foundation, SFB CRC1181 (project C01) and SFB TR221/project number 324392634 (B04) of the German Research Foundation, grants J40 and A64 of the IZKF in Erlangen, grants 2014_A47 and 2014_A184 of the Else-Kröner-Fresenius-Foundation, grant 14-12-17-1-Bergmann of the ELAN-Foundation Erlangen and a Career Support Award of Medicine of the Ernst Jung Foundation.

  • 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.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Ethics approval The samples and the analysis of those samples have been approved by the ethical committee of the University of Erlangen-Nuremberg.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data sharing not applicable as no datasets generated and/or analysed for this study. Data are available upon reasonable request. Primary data are available upon request.