Neutral Sphingomyelinase 2 (SMPD3)-Deficiency in Mice Causes Chondrodysplasia with Unimpaired Skeletal Mineralization.
Neutral Sphingomyelinase 2 (SMPD3)-Deficiency in Mice Causes Chondrodysplasia with Unimpaired Skeletal Mineralization.
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DOI：
10.1016/j.ajpath.2019.05.008
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发表时间：
2019-09
期刊：
影响因子：
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通讯作者：
W. Stoffel;Ina Hammels;B. Jenke;Inga Schmidt-Soltau;A. Niehoff
中科院分区：
文献类型：
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作者：
W. Stoffel;Ina Hammels;B. Jenke;Inga Schmidt-Soltau;A. Niehoff
中性鞘磷脂酶3（Smpd 3-/-）小鼠的SMPD 3缺陷导致一种新形式的幼年侏儒症，说明smpd 3是一种多基因决定身高的因素。SMPD 3控制高尔基体隔室中鞘磷脂循环的稳态，这对于膜重塑、启动多种形式囊泡形成和高尔基体分泌途径中的运输是必需的。使用unbiasedSmpd 3-/-遗传模型，这项研究表明，扰动的高尔基体分泌途径的骨骺生长区的软骨细胞导致dysproteostasis，骨骼生长抑制，畸形，和软骨发育不良，但显示未受损的矿化在初级和次级enchonossification中心。这已经通过Smpd 3-/-小鼠长骨的生化分析和免疫组织化学进行了阐述。外周定量计算机断层扫描、高分辨率显微计算机断层扫描显示了骨的微结构和三维结构的更精确定义，而双能X线骨密度测定法的精确度较低。化学诱变产生的fro/fro突变体8号染色体上980-kb缺失的Smpd 3位点的消融是骨骼矿化不足、骨质疏松症和长骨多发性骨折的原因，这些是人类成骨障碍的标志。本文所述的遗传上无偏倚的Smpd 3-/-小鼠的表型排除了Smpd 3作为人类成骨细胞候选基因的作用，但表明SMPD 3缺陷是一种新型软骨发育不良的发病基础。
SMPD3 deficiency in the neutral sphingomyelinase (Smpd3-/-) mouse results in a novel form of juvenile dwarfism, suggestingsmpd3is a polygenetic determinant of body height. SMPD3 controls homeostasis of the sphingomyelin cycle in the Golgi compartment, essential for membrane remodeling, initiating multiform vesicle formation and transport in the Golgi secretory pathway. Using the unbiasedSmpd3-/-genetic model, this study shows that the perturbed Golgi secretory pathway of chondrocytes of the epiphyseal growth zone leads to dysproteostasis, skeletal growth inhibition, malformation, and chondrodysplasia, but showed unimpaired mineralization in primary and secondary enchondral ossification centers. This has been elaborated by biochemical analyses and immunohistochemistry of long bones ofSmpd3-/-mice. A more precise definition of the microarchitecture and three-dimensional structure of the bone was shown by peripheral quantitative computed tomography, high-resolution microcomputed tomography, and less precisely by dual-energy X-ray absorptiometry for osteodensitometry. Ablation of theSmpd3locus as part of a 980-kb deletion on chromosome 8 in thefro/fromutant, generated by chemical mutagenesis, is held responsible for skeletal hypomineralization, osteoporosis, and multiple fractures of long bones, which are hallmarks of human osteogenesis imperfecta. The phenotype of the genetically unbiasedSmpd3-/-mouse, described here, precludes the proposed role ofSmpd3as a candidate gene of human osteogenesis imperfecta, but suggests SMPD3 deficiency as the pathogenetic basis of a novel form of chondrodysplasia.