RT Journal Article
SR Electronic
T1 Acyltransferase skinny hedgehog regulates TGFβ-dependent fibroblast activation in SSc
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 1269
OP 1273
DO 10.1136/annrheumdis-2019-215066
VO 78
IS 9
A1 Liang, Ruifang
A1 Kagwiria, Rosebeth
A1 Zehender, Ariella
A1 Dees, Clara
A1 Bergmann, Christina
A1 Ramming, Andreas
A1 Krasowska, Dorota
A1 Michalska-Jakubus, Małgorzata
A1 Kreuter, Alexander
A1 Kraner, Max E
A1 Schett, Georg
A1 Distler, Jörg H W
YR 2019
UL http://ard.bmj.com/content/78/9/1269.abstract
AB 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.