Nadine Beckmann1, Katrin Anne Becker1, Silke Walter2,3,4, Jan U Becker5, Melanie Kramer1, Gabriele Hessler1, Stefanie Weber6, Joachim R Göthert6, Klaus Fassbender2, Erich Gulbins1,7, Alexander Carpinteiro1,6. 1. Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany. 2. Department of Neurology, Saarland University, Homburg, Germany. 3. Florey Institute of Neuroscience and Mental Health and Department of Neurology, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia. 4. Neuroscience Department, Anglia Ruskin University, Chelmsford, United Kingdom. 5. eInstitute of Pathology, University Hospital Cologne, Cologne, Germany. 6. Department of Hematology, University Hospital Essen, Essen, Germany. 7. Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA.
Abstract
BACKGROUND/AIMS: Rheumatoid arthritis is a chronic autoimmune disease hallmarked by inflammation in synovial joints. Treatment is hampered by the lack of a cure and current disease-modifying drugs are associated with potentially severe toxicities. METHODS: We investigated arthritis severity by measuring joint swelling and pro-inflammatory cytokine production in a murine experimental model of inflammatory arthritis (antigen-induced arthritis). We analyzed acid sphingomyelinase knock-out mice and wild-type littermates, as well as mice treated with the pharmacological acid sphingomyelinase inhibitor amitriptyline. RESULTS: Genetic ablation or pharmacological inhibition of acid sphingomyelinase reduced joint swelling and levels of pro-inflammatory cytokines in the arthritic joint. CONCLUSION: We identified acid sphingomyelinase as a novel druggable target in rheumatoid arthritis. Functional inhibitors of acid sphingomyelinase have been clinically used for decades, are well tolerated and suitable for long-term treatment. They would be immediately available for clinical development as a novel rheumatoid arthritis therapy.
BACKGROUND/AIMS: Rheumatoid arthritis is a chronic autoimmune disease hallmarked by inflammation in synovial joints. Treatment is hampered by the lack of a cure and current disease-modifying drugs are associated with potentially severe toxicities. METHODS: We investigated arthritis severity by measuring joint swelling and pro-inflammatory cytokine production in a murine experimental model of inflammatory arthritis (antigen-induced arthritis). We analyzed acid sphingomyelinase knock-out mice and wild-type littermates, as well as mice treated with the pharmacological acid sphingomyelinase inhibitor amitriptyline. RESULTS: Genetic ablation or pharmacological inhibition of acid sphingomyelinase reduced joint swelling and levels of pro-inflammatory cytokines in the arthritic joint. CONCLUSION: We identified acid sphingomyelinase as a novel druggable target in rheumatoid arthritis. Functional inhibitors of acid sphingomyelinase have been clinically used for decades, are well tolerated and suitable for long-term treatment. They would be immediately available for clinical development as a novel rheumatoid arthritis therapy.
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