Background:The aldehyde dehydrogenase (ALDH) superfamily composes a group of 20 enzymes that catalyze aldehyde oxidation. Within this enzyme family, ALDH3A2 stands out for its central role in the oxidation of long-chain aldehydes. Of particular interest, the substrates of ALDH3A2 include also profibrotic lipid mediators such as sphingosine 1-phosphate or leukotrienes, which have been reported to be deregulated in the context of SSc.Objectives:We aimed to investigate the role of ALDH3A2 in fibrotic tissue remodeling in SSc.Methods:Fibroblast-to-myofibroblast transition was analyzed by quantification of ACTA2/αSMA, by assessment of stress fiber formation and mRNA and protein levels of type I collagens. ALDH3A2/Aldh3a2 siRNAs were employed to specifically knockdown ALDH3A2 in dermal fibroblasts both in vitro and in vivo. Overexpression of ALDH3A2 was achieved by ALDH3A2-pcDNA transfection. The role of ALDH3A2 was investigated in three different mouse models: Bleomycin- and cGvHD-induced dermal fibrosis as well as fibrosis induced by overexpression of a constitutively active TGFβ receptor I (TBRICA). Target genes of ALDH3A2 in fibroblasts were identified by RNA sequencing.Results:The expression of ALDH3A2 was modestly reduced in dermal fibroblasts of SSc skin as compared to matched healthy controls. This reduction in ALDH3A2 expression was phenocopied by activation of TGFβ signaling, whereas selective inhibition of TGFβ signaling prevented the downregulation of ALDH3A2 in experimental fibrosis. ALDH3A2 overexpression promoted fibroblast-to-myofibroblast transition with increased levels of αSMA, enhanced formation of stress fibers and reduced collagen release. In contrast, knockdown of ALDH3A2 in dermal fibroblasts inhibited fibroblast activation and collagen release. Moreover, in vivo knockdown of ALDH3A2 in the skin of mice ameliorated dermal thickening, myofibroblast differentiation and collagen deposition in three different murine models of skin fibrosis: Bleomycin-induced skin fibrosis and sclerodermatous GvHD-as models of inflammatory stages of SSc and TBRICA-induced fibrosis as an inflammation-independent model of SSc. RNA sequencing of ALDH3A2-knockdown fibroblasts demonstrated that ALDH3A2 regulates the activity of a network of profibrotic developmental pathways including TGFβ, Wnt, Notch, and Hedgehog signaling.Conclusion:We demonstrate that ALDH3A2 regulates a network of profibrotic pathways to control fibroblast activation and tissue fibrosis. ALDH3A2 is modestly downregulated in SSc fibroblasts as result of an endogenous, TGFβ-driven feedback loop. Although this modest downregulation is not sufficient to counterbalance the aberrant fibroblast activation in SSc, augmentation of this endogenous regulation by knockdown of ALDH3A2 demonstrates potent antifibrotic potential in experimental dermal fibrosis, thereby providing first evidence for ALDH3A2 as a target for antifibrotic therapies.Disclosure of Interests:Xiaohan Xu: None declared, Yi-Nan Li: None declared, Chih-Wei Chen: None declared, Thuong Trinh-Minh: None declared, Georg Schett: None declared, Jörg H.W. Distler Consultant of: Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, Grant/research support from: Anamar, Active Biotech, Array Biopharma, ARXX, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB
Background:Fibroblast growth factor receptor 3 (FGFR3) is a member of the family of different fibroblast growth factor receptors with several ligands called fibroblast growth factors (FGFs) in humans. Each FGFR has different isoforms resulting from natural alternative splice variants. Upon binding FGF ligands, fibroblast growth factor receptors (FGFRs) trigger various intracellular signaling pathways to regulate important biological processes. Systematic evaluation of FGF/FGFR signaling in the context of SSc has not been performed so far.Objectives:The aim of this study was to characterize FGFR3/FGF9 signaling in the context of fibroblast activation and to evaluate FGFR3 as a potential molecular target for antifibrotic treatment in SSc.Methods:Differential expression profiling of dermal cells from SSc patients and healthy volunteers were performed employing GEArray cDNA microarray. Real-time PCR, Western Blot, immunohistochemistry and immunofluorescence were done in skin tissues and fibroblasts from SSc patients. Selective inhibitors in conjunction with genetic knockdown and knockout strategies were used to target FGFR3 signalingin vitroand in mouse models of SSc: skin fibrosis induced by bleomycin and by overexpression of a constitutively active transforming growth factor receptor 1 (TBR) and tight skin-1 (TSK) mice. Affymetrix gene arrays in dermal fibroblasts from mice with constitutive FGFR3 signaling and mice lacking FGFR3.Results:Expression of FGFR3, specifically the isoform FGFR3IIIb and its ligand FGF9, was significantly upregulated in the dermis and dermal fibroblasts of SSc patients as compared to healthy volunteers. Furthermore, an increase of FGFR3 IIIb/FGF9 expression comparable to that in SSc fibroblasts could also be obtained by stimulating normal healthy dermal fibroblasts with transforming growth factor (TGFβ)in vitroand in mice constitutively overexpressing active TGFβ receptor type I.Transcriptome profiling,in silicoanalysis and functional experiments revealed that FGFR3 synergistigically induces multiple profibrotic pathways including Endothelin-, Interleukin-4- and CTGF-signaling in a CREB-dependent manner. FGFR3 exerts profibrotic effects by modulating phosphorylation of CREB by ERK-, AKT-, CAMK2- and p38-kinases. Activation of FGFR3 in healthy or SSc dermal fibroblasts by stimulation with recombinant FGF9 was sufficient to induce resting fibroblast-to-myofibroblast differentiation along with increased collagen secretion and alpha-SMA production.Genetic knockout of Fgfr3 abrogates myofibroblast differentiationin vitroand ameliorates skin fibrosis in TSK and TBR mice and in bleomycin-induced fibrosis. Further confirming the translational potential of these findings in the preclinical models of SSc, we demonstrate that pharmacological inactivation of FGFR3 by PD173074 could induce the regression of experimental fibrosis invitroand in bleomycin-challenged, TSK and TBR mice.Conclusion:Our findings characterize FGFR3 as an upstream regulator of a network of profibrotic mediators in SSc and thus, we could demonstrate successfully that the targeted inhibition of FGFR3 could inhibit multiple signaling pathwaysin vitroand ameliorated fibrosis in different preclinical models of SSc. These findings may have direct translational implications as FGFR3 inhibitors are currently in development.Disclosure of Interests:Debomita Chakraborty: None declared, Honglin Zhu: None declared, Astrid Juengel: None declared, Lena Summa: None declared, Yi-Nan Li: None declared, Christina Bergmann: None declared, Alexandru-Emil Matei: None declared, Thuong Trinh-Minh: None declared, Chih-Wei Chen: None declared, Clara Dees: None declared, Andreas Ramming: None declared, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Jörg Distler Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Paid instructor for: Boehringer Ingelheim, Speakers bureau: Boehringer Ingelheim
Background:Autophagy is catabolic process allowing cells to degrade unnecessary or dysfunctional cellular organelles. Failure of appropriate regulation of autophagy, however, can severely perturb tissue homeostasis. Recent studies demonstrate that autophagy is activated in several fibrotic diseases such as liver fibrosis, renal interstitial fibrosis, cardiac fibrosis.Objectives:The objective of this work was to characterize the activation of autophagy in systemic sclerosis (SSc) and to decipher its role in the pathogenesis of SSc.Methods:Activation of autophagy in skin samples of patients and murine models of SSc was assessed by co-staining of LC3B and P62 with the lysosomal marker LAMP2. The role of the autophagy was investigated in the model of bleomycin-induced dermal fibrosis. Beclin1 was overexpressed using adenovirus encoding for Beclin1. To knockdown Atg7 in vivo was achieved by subcutaneous injections of Atg7 siRNA or non-targeting siRNA. In vivo, 3-methyladenine (3-MA) was administered i.p. in a concentration of 15 mg/kg ones daily. Protein expression was measured by Western blot. Target genes were analyzed by qPCR. To monitor the autophagic flux, we generated adenoviral vectors encoding for tandem fluorescent-tagged LC3 (mRFP-EGFP-LC3).Results:In the present study, we demonstrate that autophagy is activated in fibroblasts in SSc skin and also in experimental fibrosis models as compared to respective non-fibrotic control tissue with enhanced activity in in vivo and in vitro autophagy reporter studies. The aberrant activation of autophagy had profound stimulatory effects on fibroblasts. Activation of autophagy by forced expression of BECLIN1 promoted fibroblast-to-myofibroblast transition and stimulated the collagen release by cultured human fibroblasts and induced fibrosis in murine model. Nevertheless, inhibition of autophagy can deactivate myofibroblasts and induce regression of tissue fibrosis. Knockdown of ATG7 or BECLIN1 in human fibroblasts reduced the expression of αSMA and the number of stress fibers in myofibroblasts, indicating re-differentiation of myofibroblasts into resting fibroblasts upon inhibition of autophagy. Similar results were obtained with the autophagy inhibitors CQ and 3-MA. In vivo, siRNA mediated knockdown of Atg7 effectively prevented progression of fibrosis in a model of established bleomycin-induced skin fibrosis. Inactivation of autophagy decreased dermal thickness, myofibroblast counts and hydroxyproline content to below pretreatment levels, indicating regression of bleomycin-induced skin fibrosis. In addition, treatment of mice with the autophagy inhibitor 3-MA ameliorated bleomycin-induced skin fibrosis.Conclusion:We demonstrate that autophagy activity is enhanced in fibroblasts of SSc patients and in murine models of SSc. The increased activation of autophagy induces fibroblast-to-myofibroblast transition and promotes fibrotic tissue remodeling. However, inhibition of autophagy can deactivate myofibroblasts and induce regression of tissue fibrosis.References:[1]Wynn, T. Cellular and molecular mechanisms of fibrosis. J Pathol 214, 199-210 (2008).[2]Klionsky DJ, Abeliovich H, Agostinis P, et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4, 151-175 (2008).[3]Wang, CW & Klionsky, DJ. The molecular mechanism of autophagy. Mol Med 9, 65-76 (2003).[4]Hernández-Gea V, Ghiassi-Nejad Z, Rozenfeld R, et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142, 938-946 (2012).Disclosure of Interests:Ariella Zehender: None declared, Yi-Nan Li: None declared, Neng-Yu Lin: None declared, Andrea-Hermina Györfi: None declared, Alina Soare: None declared, Christina Bergmann: None declared, Andreas Ramming: None declared, Georg Schett: None declared, Jörg H.W. Distler Consultant of: Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB., Grant/research support from: Anamar, Active Biotech, Array Biopharma, aTyr, BMS, Bayer Pharma, Boehringer Ingel-heim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB., Employee of: stock owner of 4D Science and Scientific head of FibroCure
Background:Autophagy is catabolic process allowing cells to degrade unnecessary or dysfunctional cellular organelles. Failure of appropriate regulation of autophagy, however, can severely perturb tissue homeostasis. Several stimuli present in fibrosis such as pro-fibrotic cytokines are known to activate autophagy.Objectives:The objective of this work was to characterize the regulation of autophagy in systemic sclerosis (SSc) and to decipher its role in the pathogenesis of SSc.Methods:Activation of autophagy in SSc skin and matched tissue samples from healthy individuals was assessed by immunofluorescence staining for ATG7, BECLIN1 and P62. We generatedAtg7fl/flxCol1a2;CreER mice to selectively disable autophagy in fibroblasts. The role of the autophagy was investigated in the model of bleomycin- and TβRIact-induced dermal and pulmonary fibrosis. Overexpression of Myst1 was achieved by adenovirus encoding forMyst1. Collagen release and protein expression were measure by Western blot. Target genes were analyzed by RT-PCR. Co-immunoprecipitation and reporter assay were performed to study physical and functional interactions between MYST1 and SMAD3. To monitor the autophagic fluxin vitroandin vivowe generated adenoviral vectors encoding for tandem fluorescent-tagged LC3 (mRFP-EGFP-LC3).Results:Transforming growth factor-β (TGFβ) activates autophagy by an epigenetic mechanism to amplify its profibrotic effects. TGFβ induces autophagy in fibrotic diseases by SMAD3-dependent downregulation of the H4K16 histone acetyltransferase MYST1, which regulates the expression of core components of the autophagy machinery such as ATG7 and BECLIN1. Activation of autophagy in fibroblasts promotes collagen release and is both, sufficient and required, to induce tissue fibrosis. Forced expression of MYST1 abrogates the stimulatory effects of TGFβ on autophagy and re-establishes the epigenetic control of autophagy in fibrotic conditions. Interference with the aberrant activation of autophagy inhibits TGFβ-induced fibroblast activation and ameliorates experimental dermal and pulmonary fibrosis. These findings link uncontrolled TGFβ signaling to aberrant autophagy, deregulated epigenetics in fibrotic diseases and may open new avenues for therapeutic intervention in fibrotic diseases.Conclusion:We demonstrate that the epigenetic control of autophagy is disturbed by a TGFβ-dependent downregulation of the H4K16 histone acetyltransferase MYST1. The increased activation of autophagy induces fibroblast-to-myofibroblast transition and promotes fibrotic tissue remodeling. Re-expression of MYST1 prevents aberrant autophagy, limits the profibrotic effects of TGFβ and ameliorates experimental fibrosis. Restoration of the epigenetic control of autophagy might thus be a novel approach to ameliorate fibrotic tissue remodeling.References:[1]Wynn, T.A. Cellular and molecular mechanisms of fibrosis. J Pathol 214, 199-210 (2008).[2]Distler, J.H., et al. Review: Frontiers of Antifibrotic Therapy in Systemic Sclerosis. Arthritis & rheumatology (Hoboken, N.J.) 69, 257-267 (2017).[3]Gyorfi, A.H., Matei, A.E. & Distler, J.H.W. Targeting TGF-beta signaling for the treatment of fibrosis. Matrix biology: journal of the International Society for Matrix Biology 68-69, 8-27 (2018).[4]Wang, C.W. & Klionsky, D.J. The molecular mechanism of autophagy. Mol Med 9, 65-76 (2003).[5]Hernandez-Gea, V., et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142, 938-946 (2012).Disclosure of Interests:Ariella Zehender: None declared, Neng Yu Lin: None declared, Yi-Nan Li: None declared, Andrea-Hermina Györfi: None declared, Christina Bergmann: None declared, Andreas Ramming Grant/research support from: Pfizer, Novartis, Consultant of: Boehringer Ingelheim, Novartis, Gilead, Pfizer, Speakers bureau: Boehringer Ingelheim, Roche, Janssen, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Jörg Distler Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Paid instructor for: Boehringer Ingelheim, Speakers bureau: Boehringer Ingelheim
Background:Bone remodeling is a constant process maintained by the balance between osteoclast-triggered bone resorption and osteoblast-mediated bone formation. In inflammatory arthritis, such as rheumatoid arthritis (RA), the pro-inflammatory environment favors osteoclast differentiation and skews the balance towards resorption, leading to progressive bone erosion and bone loss. O-GlcNAcylation is a post-translational modification, which transfers a single N-acetylglucosamine molecule to the serine or threonine of the target protein. The modification is accomplished by a single pair of enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Unlike other glycosylation, O-GlcNAcylation occurs in multiple cellular compartments, including the nucleus. Although O-GlcNAcylation is one of the most common modifications, its role in bone homeostasis is still poorly understood.Objectives:We aimed to investigate the role of O-GlcNAcylation in osteoclastogenesis under pro-inflammatory milieus. We also focused on dissecting the signaling pathways affected by O-GlcNAcylation during osteoclast differentiation.Methods:We examined the levels of O-GlcNAc during in vitro osteoclastogenesis by western blotting. The levels of O-GlcNAc in tissue from RA patients and experimental arthritis were detected by immunofluorescence. Pharmacological inhibition and genetic knockout were used to manipulate O-GlcNAcylaiton during osteoclastogenesis. RNA sequencing was performed to study O-GlcNAc-mediated pathways.Results:We demonstrate the dynamic changes in O-GlcNAcylation during osteoclastogenesis. The elevated O-GlcNAcylation was found in the early differentiation stages, whereas its downregulation was detected in the maturation process. TNFα elaborates the dynamic changes in O-GlcNAcylation, which further intensifies osteoclast differentiation.Targeting OGT by selective inhibitor and genetic knockout restrain O-GlcNAcylation and hinder the expression of the early differentiation marker Nfatc1. Inhibition of OGA, which forces high levels of O-GlcNAcylation throughout the differentiation, reduces the formation of multinucleated mature osteoclasts. Consistent with our in vitro data, suppressing OGT and OGA both ameliorate bone loss in experimental arthritis. We detected a reduced number of TRAP-expressing precursors and mature osteoclasts in the mice subjected to OGT inhibition. While inhibiting OGA only lowers the number of TRAP+F4/80– mature osteoclasts without affecting the number of TRAP+F4/80+ precursors.Transcriptome profiling reveals that O-GlcNAcylation regulates several biological processes. Increased O-GlcNAcylation promotes cytokine signaling and oxidative phosphorylation. The downregulation of O-GlcNAcylation is essential for cytoskeleton organization and cell fusion.Conclusion:We demonstrate that the dynamic changes of O-GlcNAcylation are essential for osteoclast differentiation. These findings reveal the therapeutic potential of targeting O-GlcNAcylation in pathologic bone resorption.Disclosure of Interests:Chih-Wei Chen: None declared, Yi-Nan Li: None declared, Thuong Trinh-Minh: None declared, ZHU Honglin: None declared, Alexandru-Emil Matei: None declared, Xiao Ding: None declared, Cuong Tran Manh: None declared, Xiaohan Xu: None declared, Christoph Liebel: None declared, Ruifang Liang: None declared, Min-Chuan Huang: None declared, Neng-Yu Lin: None declared, Andreas Ramming Speakers bureau: Boehringer Ingelheim, Roche, Janssen, Consultant of: Boehringer Ingelheim, Novartis, Gilead, Pfizer, Grant/research support from: Pfizer, Novartis, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Jörg H.W. Distler Shareholder of: 4D Science, Speakers bureau: Boehringer Ingelheim, Paid instructor for: Boehringer Ingelheim, Consultant of: Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, Grant/research support from: Anamar, Active Biotech, Array Biopharma, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB, Employee of: FibroCure
Background:The complex pathophysiological processes that result in fibrotic tissue remodeling in systemic sclerosis involve interplay between multiple cell types (1). Experimental models of fibrosis are essential to provide a conceptual understanding of the pathogenesis of these diseases and to test antifibrotic drugs. Current models of fibrosis have important limitations: thein vivomodels rely on species that are phylogenetically distant, whereas thein vitromodels are oversimplified cultures of a single cell type in an artificial two-dimensional environment of excessive stiffness, which imposes an unphysiological cell polarization (2).Objectives:Here we evaluated the potential use of vascularized, three-dimensionalin vitrohuman skin equivalents as a novel model of skin fibrosis and a platform for the evaluation of antifibrotic drugs.Methods:Skin equivalents were generated by seeding human endothelial cells, fibroblasts and keratinocytes on a decellularized porcine extracellular matrix with perfusable vascular structure. The skin models were cultured for one month in a system that ensured perfusion of the vascular network at physiological pressure. Fibrotic transformation induced by TGFβ and response to nintedanib as an established antifibrotic drug was evaluated by capillary Western immunoassays, qPCR, histology and immunostaining.Results:The vascularized human skin equivalents formed the major skin structures relevant for the pathogenesis of fibrosis: a polarized, fully matured epidermis, a stratified dermis and a perfused vessel system with small capillaries. Exposure to TGFβ led to the fibrotic transformation of the skin equivalents, with activated TGFβ downstream pathways, increased fibroblast-to-myofibroblast transition and excessive deposition of extracellular matrix. Treatment of models exposed to TGFβ with nintedanib (a drug with proven antifibrotic effects) ameliorated the fibrotic transformation of skin equivalents with reduced TGFβ signaling, fibroblast-to-myofibroblast transition and decreased extracellular matrix deposition.Conclusion:Here we describe a novelin vitromodel of skin fibrosis. Our data show that vascularized skin equivalents can reproduce all skin layers affected by fibrosis, that, upon exposure to TGFβ, these models recapitulate key features of fibrotic skin and that these skin models can be used as a platform for evaluation of antifibrotic drugs in a setting with high relevance for human disease.References:[1]Distler JHW, Gyorfi AH, Ramanujam M, Whitfield ML, Konigshoff M, Lafyatis R. Shared and distinct mechanisms of fibrosis. Nature reviews Rheumatology. 2019;15(12):705-30.[2]Garrett SM, Baker Frost D, Feghali-Bostwick C. The mighty fibroblast and its utility in scleroderma research. Journal of scleroderma and related disorders. 2017;2(2):69-134.Disclosure of Interests:Alexandru-Emil Matei: None declared, Chih-Wei Chen: None declared, Lisa Kiesewetter: None declared, Andrea-Hermina Györfi: None declared, Yi-Nan Li: None declared, Thuong Trinh-Minh: None declared, Toin van Kuppevelt: None declared, Jan Hansmann: None declared, Astrid Juengel: None declared, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Florian Groeber-Becker: None declared, Jörg Distler Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Paid instructor for: Boehringer Ingelheim, Speakers bureau: Boehringer Ingelheim
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