PT  - JOURNAL ARTICLE
AU  - Yun Zhang
AU  - Sebastian Pötter
AU  - Chih-Wei Chen
AU  - Ruifang Liang
AU  - Kolja Gelse
AU  - Ingo Ludolph
AU  - Raymund E Horch
AU  - Oliver Distler
AU  - Georg Schett
AU  - Jörg H W Distler
AU  - Clara Dees
TI  - Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis
AID  - 10.1136/annrheumdis-2017-212265
DP  - 2018 May 01
TA  - Annals of the Rheumatic Diseases
PG  - 744--751
VI  - 77
IP  - 5
4099  - http://ard.bmj.com/content/77/5/744.short
4100  - http://ard.bmj.com/content/77/5/744.full
SO  - Ann Rheum Dis2018 May 01; 77
AB  - Objectives The enzyme poly(ADP-ribose) polymerase-1 (PARP-1) transfers negatively charged ADP-ribose units to target proteins. This modification can have pronounced regulatory effects on target proteins. Recent studies showed that PARP-1 can poly(ADP-ribosyl)ate (PARylate) Smad proteins. However, the role of PARP-1 in the pathogenesis of systemic sclerosis (SSc) has not been investigated.Methods The expression of PARP-1 was determined by quantitative PCR and immunohistochemistry. DNA methylation was analysed by methylated DNA immunoprecipitation assays. Transforming growth factor-β (TGFβ) signalling was assessed using reporter assays, chromatin immunoprecipitation assays and target gene analysis. The effect of PARP-1 inactivation was investigated in bleomycin-induced and topoisomerase-induced fibrosis as well as in tight-skin-1 (Tsk-1) mice.Results The expression of PARP-1 was decreased in patients with SSc, particularly in fibroblasts. The promoter of PARP-1 was hypermethylated in SSc fibroblasts and in TGFβ-stimulated normal fibroblasts. Inhibition of DNA methyltransferases (DNMTs) reduced the promoter methylation and reactivated the expression of PARP-1. Inactivation of PARP-1 promoted accumulation of phosphorylated Smad3, enhanced Smad-dependent transcription and upregulated the expression of TGFβ/Smad target genes. Inhibition of PARP-1 enhanced the effect of TGFβ on collagen release and myofibroblast differentiation in vitro and exacerbated experimental fibrosis in vivo. PARP-1 deficiency induced a more severe fibrotic response to bleomycin with increased dermal thickening, hydroxyproline content and myofibroblast counts. Inhibition of PARylation also exacerbated fibrosis in Tsk-1 mice and in mice with topoisomerase-induced fibrosis.Conclusion PARP-1 negatively regulates canonical TGFβ signalling in experimental skin fibrosis. The downregulation of PARP-1 in SSc fibroblasts may thus directly contribute to hyperactive TGFβ signalling and to persistent fibroblast activation in SSc.