Graduate School of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwaicho, Fuchu, Tokyo 183-8509, Japan.
Laboratory of Veterinary Anatomy, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501, Hokkaido, Japan.
Genes (Basel). 2023 Jan 24;14(2):308. doi: 10.3390/genes14020308.
Loss-of-function mutations in () cause musculocontractural Ehlers-Danlos syndrome- (mcEDS-), characterized by multiple congenital malformations and progressive connective tissue fragility-related manifestations in the cutaneous, skeletal, cardiovascular, visceral and ocular system. The replacement of dermatan sulfate chains on decorin proteoglycan with chondroitin sulfate chains is proposed to lead to the disorganization of collagen networks in the skin. However, the pathogenic mechanisms of mcEDS- are not fully understood, partly due to the lack of in vitro models of this disease. In the present study, we established in vitro models of fibroblast-mediated collagen network formation that recapacitate mcEDS- pathology. Electron microscopy analysis of mcEDS--mimicking collagen gels revealed an impaired fibrillar organization that resulted in weaker mechanical strength of the gels. The addition of decorin isolated from patients with mcEDS- and mice disturbed the assembly of collagen fibrils in vitro compared to control decorin. Our study may provide useful in vitro models of mcEDS- to elucidate the pathomechanism of this disease.
（）功能丧失突变导致肌肉骨骼型埃勒斯-当洛斯综合征（mcEDS-），其特征是多种先天性畸形和进行性结缔组织脆弱性相关表现，涉及皮肤、骨骼、心血管、内脏和眼部系统。拟议用硫酸软骨素链替代聚集蛋白聚糖上的硫酸皮肤素链，导致皮肤胶原网络的紊乱。然而，mcEDS-的发病机制尚不完全清楚，部分原因是缺乏该疾病的体外模型。在本研究中，我们建立了体外成纤维细胞介导的胶原网络形成模型，再现了 mcEDS-的病理学特征。对模仿 mcEDS-的胶原凝胶的电子显微镜分析显示，纤维组织的排列受损，导致凝胶的机械强度减弱。与对照聚集蛋白聚糖相比，从 mcEDS-患者和 小鼠中分离出的聚集蛋白聚糖在体外扰乱了胶原原纤维的组装。我们的研究可能为 mcEDS-提供有用的体外模型，以阐明该疾病的发病机制。
