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Acyltransferase skinny hedgehog regulates TGFβ-dependent fibroblast activation in SSc
  1. Ruifang Liang1,
  2. Rosebeth Kagwiria1,
  3. Ariella Zehender1,
  4. Clara Dees1,
  5. Christina Bergmann1,
  6. Andreas Ramming1,
  7. Dorota Krasowska2,
  8. Małgorzata Michalska-Jakubus2,
  9. Alexander Kreuter3,
  10. Max E Kraner4,
  11. Georg Schett1,
  12. Jörg H W Distler1
  1. 1 Department of Internal Medicine 3- Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Bayern, Germany
  2. 2 Department of Dermatology, Venereology and Pediatric Dermatology, Medical University of Lublin, Lublin, Poland
  3. 3 Department of Dermatology, Venereolog and Allergology, HELIOS St Elisabeth Hospital Oberhausen, University Witten-Herdecke, Oberhausen, Germany
  4. 4 Department of Biology, Division of Biochemistry, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
  1. Correspondence to Dr Jörg H W Distler, Department of Internal Medicine III, University of Erlangen, Erlangen D-91054, Germany; joerg.distler{at}


Objectives Systemic sclerosis (SSc) is characterised by aberrant hedgehog signalling in fibrotic tissues. The hedgehog acyltransferase (HHAT) skinny hedgehog catalyses the attachment of palmitate onto sonic hedgehog (SHH). Palmitoylation of SHH is required for multimerisation of SHH proteins, which is thought to promote long-range, endocrine hedgehog signalling. The aim of this study was to evaluate the role of HHAT in the pathogenesis of SSc.

Methods Expression of HHAT was analysed by real-time polymerase chain reaction(RT-PCR), immunofluorescence and histomorphometry. The effects of HHAT knockdown were analysed by reporter assays, target gene studies and quantification of collagen release and myofibroblast differentiation in cultured human fibroblasts and in two mouse models.

Results The expression of HHAT was upregulated in dermal fibroblasts of patients with SSc in a transforming growth factor-β (TGFβ)/SMAD-dependent manner. Knockdown of HHAT reduced TGFβ-induced hedgehog signalling as well as myofibroblast differentiation and collagen release in human dermal fibroblasts. Knockdown of HHAT in the skin of mice ameliorated bleomycin-induced and topoisomerase-induced skin fibrosis.

Conclusion HHAT is regulated in SSc in a TGFβ-dependent manner and in turn stimulates TGFβ-induced long-range hedgehog signalling to promote fibroblast activation and tissue fibrosis. Targeting of HHAT might be a novel approach to more selectively interfere with the profibrotic effects of long-range hedgehog signalling.

  • skinny hedgehog
  • systemic sclerosis
  • hedgehog signaling
  • TGFβ
  • dermal fibrosis

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  • Handling editor Josef S Smolen

  • Contributors RL and JHWD designed the study. RL, RK, MEK and AZ were involved in acquisition of data. RL, RK, AZ, CD, CB, AR, MEK, GS and JHWD were involved in interpretation of data. RL and JHWD were involved in manuscript preparation. DK, MM-J and AK provided essential samples.

  • Funding Grants DI 1537/7-1, DI 1537/8-1, DI 1537/9-1 and -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, grant 2013.056.1 of the Wilhelm-Sander-Foundation, 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 consent for publication Not required.

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

  • Data availability statement All data relevant to the study are included in the article or uploaded as online supplementary information.