Zebrafish enpp1 mutants exhibit pathological mineralization, mimicking features of generalized arterial calcification of infancy (GACI) and pseudoxanthoma elasticum (PXE).
Zebrafish enpp1 mutants exhibit pathological mineralization, mimicking features of generalized arterial calcification of infancy (GACI) and pseudoxanthoma elasticum (PXE).
复制标题
DOI：
10.1242/dmm.015693
复制
发表时间：
2014-07
影响因子：
4.3
通讯作者：
Schulte-Merker S
中科院分区：
文献类型：
--
作者：
Apschner A;Huitema LF;Ponsioen B;Peterson-Maduro J;Schulte-Merker S
近年来，已经清楚的是，从机械上讲，生物矿化是一个必须作为默认状态被积极抑制的过程。这种抑制必须以严格控制的方式释放，以便在骨骼元素和牙齿中发生矿化。这一概念的一个核心方面是严格控制磷酸盐（生物矿物羟基磷灰石的一种成分）和焦磷酸盐（矿化的一种理化抑制剂）之间的平衡。在这里，我们提供了一个详细的分析斑马鱼突变体，龙鱼（dgf），这是突变的外核苷焦磷酸酶/磷酸二酯酶1（Enpp 1），蛋白质，这是至关重要的供应细胞外焦磷酸。婴儿全身性动脉钙化（GACI）是一种致命的人类疾病，大多数病例被认为是由ENPP 1突变引起的。此外，一些弹性假黄瘤（pseudoxanthoma elasticum，PXE）的病例最近被认为与ENPP 1有关。与人类相似，我们在这里展示了斑马鱼enpp 1突变体可以在各种软组织中发生异位钙化-最明显的是在皮肤，软骨元素，心脏，颅内空间和脊索片中。使用转基因报告细胞系，我们表明，异位矿化在这些组织中发生的典型成骨细胞或软骨标志物的表达独立。有趣的是，我们检测到细胞表达破骨细胞标记陷阱和组织蛋白酶K在异位钙化的网站在时间点时，破骨细胞还不存在于野生型兄弟姐妹。用双膦酸盐依替膦酸盐治疗挽救了dgf表型的某些方面，我们检测到参与磷酸盐稳态和矿化的基因表达失调，如fgf 23，npt 2a，entpd 5和spp 1（也称为骨桥蛋白）。采用UAS-GalFF的方法，我们表明，在血管或突变胚胎的底板中强制表达enpp 1足以拯救脊索矿化表型。这表明enpp 1可以在远离其表达位点的组织中发挥其功能。
In recent years it has become clear that, mechanistically, biomineralization is a process that has to be actively inhibited as a default state. This inhibition must be released in a rigidly controlled manner in order for mineralization to occur in skeletal elements and teeth. A central aspect of this concept is the tightly controlled balance between phosphate, a constituent of the biomineral hydroxyapatite, and pyrophosphate, a physiochemical inhibitor of mineralization. Here, we provide a detailed analysis of a zebrafish mutant, dragonfish (dgf), which is mutant for ectonucleoside pyrophosphatase/phosphodiesterase 1 (Enpp1), a protein that is crucial for supplying extracellular pyrophosphate. Generalized arterial calcification of infancy (GACI) is a fatal human disease, and the majority of cases are thought to be caused by mutations in ENPP1. Furthermore, some cases of pseudoxanthoma elasticum (PXE) have recently been linked to ENPP1. Similar to humans, we show here that zebrafish enpp1 mutants can develop ectopic calcifications in a variety of soft tissues – most notably in the skin, cartilage elements, the heart, intracranial space and the notochord sheet. Using transgenic reporter lines, we demonstrate that ectopic mineralizations in these tissues occur independently of the expression of typical osteoblast or cartilage markers. Intriguingly, we detect cells expressing the osteoclast markers Trap and CathepsinK at sites of ectopic calcification at time points when osteoclasts are not yet present in wild-type siblings. Treatment with the bisphosphonate etidronate rescues aspects of the dgf phenotype, and we detected deregulated expression of genes that are involved in phosphate homeostasis and mineralization, such as fgf23, npt2a, entpd5 and spp1 (also known as osteopontin). Employing a UAS-GalFF approach, we show that forced expression of enpp1 in blood vessels or the floorplate of mutant embryos is sufficient to rescue the notochord mineralization phenotype. This indicates that enpp1 can exert its function in tissues that are remote from its site of expression.
登录
查看更多内容
影响因子：
3
作者：
Aiba, Atsuomi;Nakajima, Arata;Yamazaki, Masashi
通讯作者：
Yamazaki, Masashi
影响因子：
4.6
作者：
Hammond, Christina Lindsey;Schulte-Merker, Stefan
通讯作者：
Schulte-Merker, Stefan
斑马鱼COL2A1A基因的进化保守调节元件的鉴定。
影响因子：
2.7
作者：
Dale RM;Topczewski J
通讯作者：
Topczewski J
影响因子：
5.4
作者：
d'Alençon CA;Peña OA;Wittmann C;Gallardo VE;Jones RA;Loosli F;Liebel U;Grabher C;Allende ML
通讯作者：
Allende ML
影响因子：
3.6
作者：
Edouard, Thomas;Chabot, Gilles;Alos, Nathalie
通讯作者：
Alos, Nathalie