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首页> 外文期刊>Biochemical Pharmacology >Improvement of the skeletal phenotype in a mouse model of diastrophic dysplasia after postnatal treatment with N-acetylcysteine
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Improvement of the skeletal phenotype in a mouse model of diastrophic dysplasia after postnatal treatment with N-acetylcysteine

机译：基于N-乙酰半胱氨酸后宿律发育性小鼠模型骨骼表型的改进

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Diastrophic dysplasia (DTD) is a recessive chondrodysplasia caused by mutations in the SLC26A2 gene encoding for a sulfate/chloride transporter. When SLC26A2 is impaired intracellular level of sulfate is reduced leading to the synthesis of undersulfated proteoglycans. In normal chondrocytes, the main source of intracellular sulfate is the extracellular uptake through SLC26A2, but a small amount comes from the catabolism of sulfur-containing amino acids and other thiols. Here N-acetylcysteine (NAC), an extensively used drug, is proposed as alternative source of intracellular sulfate in an animal model of DTD (dtd mouse). Mutant and wild type mice were treated twice a day with hypodermic injections of 250 mg NAC/kg body weight for one week after birth. At the end of the treatment, an improvement trend in cartilage proteoglycan sulfation and in the skeletal phenotype of treated dtd mice were observed. Thus, a longer treatment lasted three weeks starting from birth was performed. Treated mutant mice showed a significant increase of cartilage proteoglycan sulfation and a relevant improvement of the skeletal phenotype based on measurements of several bony elements and bone quality by DEXA and micro CT. Moreover, the amelioration of the overall growth plate morphology in treated dtd mice suggested a partial rescue of the endochondral ossification process. Overall, the results prove that NAC is an effective source of intracellular sulfate for dtd mice in the postnatal period. This finding paves the way for a potential pharmacological treatment of DTD patients taking advantage from a drug repositioning strategy.
机译：律学发育不良（DTD）是由编码硫酸盐/氯化物转运蛋白的SLC26A2基因中的突变引起的隐性软骨细胞抑制。当SLC26A2受损时，细胞内硫酸盐水平降低，导致过硫化蛋白增生糖基因组合。在正常软骨细胞中，细胞内硫酸盐的主要来源是通过SLC26A2的细胞外摄取，但少量来自含硫氨基酸和其他硫醇的分解代谢。这里，在DTD（DTD小鼠）的动物模型中，提出了一种乙酰半胱氨酸（NAC）作为细胞内硫酸盐的替代来源。突变和野生型小鼠每天进行两次，分娩后的250mg NAC / kg体重的皮下注射注射。在治疗结束时，观察到软骨蛋白多糖硫化的改善趋势和处理的DTD小鼠的骨骼表型。因此，持续时间持续三周从出生开始。经处理的突变小鼠显示出在德克萨和微型CT的几个骨元素和骨质质量的测量结果上显着增加了软骨蛋白多糖硫化和骨骼表型的相关改善。此外，治疗DTD小鼠中总体生长板形态的改善表明了内核骨化过程的部分抢救。总体而言，结果证明NAC是在产后后期DTD小鼠的细胞内硫酸盐的有效来源。该发现为潜在的药理学治疗DTD患者的药物治疗，从药物重新定位策略中获得潜在的药理学治疗方法。

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