Beckmann Nadine, Becker Katrin Anne, Walter Silke, Becker Jan U, Kramer Melanie, Hessler Gabriele, Weber Stefanie, Göthert Joachim R, Fassbender Klaus, Gulbins Erich, Carpinteiro Alexander
Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
Department of Neurology, Saarland University, Homburg, Germany.
Cell Physiol Biochem. 2017;43(4):1460-1471. doi: 10.1159/000481968. Epub 2017 Oct 16.
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.
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.
Genetic ablation or pharmacological inhibition of acid sphingomyelinase reduced joint swelling and levels of pro-inflammatory cytokines in the arthritic joint.
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.
背景/目的：类风湿性关节炎是一种慢性自身免疫性疾病，其特征是滑膜关节炎症。由于缺乏治愈方法，治疗受到阻碍，并且目前的病情改善药物存在潜在的严重毒性。
我们通过测量炎症性关节炎（抗原诱导性关节炎）小鼠实验模型中的关节肿胀和促炎细胞因子产生来研究关节炎的严重程度。我们分析了酸性鞘磷脂酶基因敲除小鼠和野生型同窝小鼠，以及用酸性鞘磷脂酶药理抑制剂阿米替林治疗的小鼠。
酸性鞘磷脂酶的基因敲除或药理抑制降低了关节炎关节的肿胀和促炎细胞因子水平。
我们确定酸性鞘磷脂酶是类风湿性关节炎中一个新的可药物作用靶点。酸性鞘磷脂酶的功能性抑制剂已在临床上使用了数十年，耐受性良好且适合长期治疗。它们可立即用于作为一种新型类风湿性关节炎疗法的临床开发。
