POS0425 INCREASED KERATIN 9 EXPRESSION IN SYSTEMIC SCLEROSIS SKIN IS DRIVEN BY THE lncRNA HOTAIR FROM FIBROBLAST DERIVED EXOSOMES

Background: Skin fibrosis is the hallmark fibrotic manifestation of systemic sclerosis (SSc). Despite a key role tissue fibroblasts, skin changes extend to keratinocyte layer, which contribute loss function. RNA seq. analysis SSc patient forearm showed that palmoplantar specific Keratin 9 (CK9) was highly expressed (1). affected shares several features with including increased layer thickness and lack hair. Seminal work last decade has shown long noncoding in HOX loci play crucial differentiation (2), lncRNA HOTAIR being one mostly region. Objectives: Following recent data suggesting profibrotic phenotype dermal fibroblasts (3), here we set out determine if contributing factor high levels CK9 found Methods: Full-thickness biopsies were surgically obtained from forearms patients onset. Fibroblasts isolated cultured monolayers. transcript antisense (HOTAIR) healthy by lentiviral induction employing vector containing sequence. Exosomes fibroblast media using Total exosome isolation reagent (Thermo Fisher). Enhancer zeste 2 (EZH2) blocked GSK126 inhibitor. equivalents created scramble expressing primary keratinocytes Results: Media both induced expression vitro . In addition, induces 3D equivalent models. fractionation studies indicated present exosomes at higher concentration (2.7 fold p=0.01) fibroblasts. Importantly, transfection Exosomal RNAs could reproduce increase keratinocytes. Mechanistically, mediated histone methylation profile through EZH2. Conclusion: Pro-fibrotic overall function inducing adjacent transfer non-coding HOTAIR. Unraveling crosstalk activated cells may lead identify therapeutic targets re-establish homeostasis during fibrosis. References: [1]Assassi S et.al Arthritis Rheumatology 2015 [2]Rinn JL Cell 2007 [3]Wasson CW Annals Rheumatic Disease 2020 Disclosure Interests: Chris Wasson: None declared, rebecca ross: Jessica Bryon: Francesco Del Galdo Speakers bureau: Astra-Zeneca, Boehringer Ingelheim, Actelion, Consultant of: Mitsubishi-Tanabe, Capella Biosciences, Chemomab, Boehringer-Ingelheim, Grant/research support from: Kymab, Mitsubishi-Tanabe