دورية أكاديمية
أعرض في EDS

Acyltransferase skinny hedgehog regulates TGFβ-dependent fibroblast activation in SSc.

التفاصيل البيبلوغرافية
العنوان: Acyltransferase skinny hedgehog regulates TGFβ-dependent fibroblast activation in SSc.
المؤلفون: Liang R; Department of Internal Medicine 3- Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Bayern, Germany., Kagwiria R; Department of Internal Medicine 3- Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Bayern, Germany., Zehender A; Department of Internal Medicine 3- Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Bayern, Germany., Dees C; Department of Internal Medicine 3- Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Bayern, Germany., Bergmann C; Department of Internal Medicine 3- Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Bayern, Germany., Ramming A; Department of Internal Medicine 3- Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Bayern, Germany., Krasowska D; Department of Dermatology, Venereology and Pediatric Dermatology, Medical University of Lublin, Lublin, Poland., Michalska-Jakubus M; Department of Dermatology, Venereology and Pediatric Dermatology, Medical University of Lublin, Lublin, Poland., Kreuter A; Department of Dermatology, Venereolog and Allergology, HELIOS St Elisabeth Hospital Oberhausen, University Witten-Herdecke, Oberhausen, Germany., Kraner ME; Department of Biology, Division of Biochemistry, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany., Schett G; Department of Internal Medicine 3- Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Bayern, Germany., Distler JHW; Department of Internal Medicine 3- Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Bayern, Germany joerg.distler@uk-erlangen.de.
المصدر: Annals of the rheumatic diseases [Ann Rheum Dis] 2019 Sep; Vol. 78 (9), pp. 1269-1273. Date of Electronic Publication: 2019 Jun 08.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BMJ Country of Publication: England NLM ID: 0372355 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1468-2060 (Electronic) Linking ISSN: 00034967 NLM ISO Abbreviation: Ann Rheum Dis Subsets: MEDLINE
أسماء مطبوعة: Publication: London : BMJ
Original Publication: London : H.K. Lewis
مواضيع طبية MeSH: Gene Expression Regulation*, Acyltransferases/*genetics , RNA/*genetics , Scleroderma, Systemic/*genetics , Skin/*pathology , Transforming Growth Factor beta/*metabolism, Acyltransferases/biosynthesis ; Adult ; Aged ; Animals ; Blotting, Western ; Cell Differentiation ; Cells, Cultured ; Disease Models, Animal ; Female ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Humans ; Male ; Mice ; Middle Aged ; Scleroderma, Systemic/metabolism ; Scleroderma, Systemic/pathology ; Signal Transduction ; Skin/metabolism ; Young Adult
مستخلص: 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.
Competing Interests: 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.
(© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)
فهرسة مساهمة: Keywords: TGFβ; dermal fibrosis; hedgehog signaling; skinny hedgehog; systemic sclerosis
المشرفين على المادة: 0 (Transforming Growth Factor beta)
63231-63-0 (RNA)
EC 2.3.- (Acyltransferases)
EC 2.3.1.- (HHAT protein, human)
تواريخ الأحداث: Date Created: 20190610 Date Completed: 20200331 Latest Revision: 20200331
رمز التحديث: 20240628
DOI: 10.1136/annrheumdis-2019-215066
PMID: 31177096
قاعدة البيانات: MEDLINE
الوصف
تدمد:1468-2060
DOI:10.1136/annrheumdis-2019-215066