P059 Dissecting the role of gremlin 1 in systemic sclerosis
Authors: L Duffy, S O’Reilly
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Student for a master or a PhD. <h3>Introduction</h3> Systemic Sclerosis (SSc) is a multi-system autoimmune disease, its exact aetiology remains unknown. Despite its heterogeneity, SSc is characterised by three common hallmarks; vascular disruption, production of auto-antibodies and aberrent accumulation of extra cellular matrix (ECM) proteins, leading to fibrosis. Unfortunately, the disease has no cure and few effective therapies.<sup>1</sup> The aberrent regulation of developmental pathways, including that of bone morphogenetic proteins (BMP) and Gremlin 1, could yield alternative therapuetic targets. Gremlin 1 is a known BMP antagonist. However, research has found it is implicated in several pathologies including fibrotic diseases such as idiopathic pulmonary fibrosis.<sup>2</sup> A paper published in 2014 showed that recombinant Gremlin 1 is pro-fibrotic in normal human dermal fibroblasts (NHDF).<sup>3</sup> <h3>Objectives</h3> The aim is to investigate the role Gremlin 1 plays in the development of fibrosis in patients with SSc. The key steps to achieving this will involve firstly confirming overexpression of Gremlin 1 leads to an increase in key ECM proteins. <h3>Methods</h3> Once confirmed chemical, RNA and clinical antibody interference work will be carried out. Several key molecular techniques will be utilised in the project including transfection, western blotting and reverse transcription polymerase chain reaction. <h3>Results</h3> Electroporation was used to transfect NHDF with a Gremlin 1 overexpression vector. Gremlin 1 overexpression showed an increase in Collagen 1 and a statistically significant increase in the myofibroblast marker Alpha Smooth Muscle Actin, compared to control. RNAi work is currently being carried out to asses novel downstream targets. Data suggests cross-talk between the transforming growth factor beta pathway, interaction of Gremlin 1 directly with the vascular endothelial growth factor receptor or a feedback loop involving sonic hedgehog could be involved in the pathway. <h3>Conclusions</h3> Due to the rarity, lack of effective therapies and incomplete knowledge of its aetiology research into SSc is required in order to enhance understanding and therapeutic options. <h3>References</h3> Kowal-Bielecka O, Landewé R, Avouac J, Chwiesko S, Miniati I, Czirjak L, <i>et al</i>. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). <i>Annals of the Rheumatic Diseases</i> 2009;68(5):620–8. Brazil DP, Church RH, Surae S, Godson C, Martin F. BMP signalling: agony and antagony in the family. <i>Trends in Cell Biology</i> 2015;25(5):249–64. O'Reilly S, Ciechomska M, Cant R, van Laar JM. Interleukin-6 (IL-6) trans signaling drives a STAT3-dependent pathway that leads to hyperactive transforming growth factor-β (TGF-β) signaling promoting SMAD3 activation and fibrosis via Gremlin protein. <i>Journal of Biological Chemistry</i> 2014;289(14):9952–60. <h3>Disclosure of Interest</h3> None declared.