Aberrant mineralization of connective tissues in a mouse model of pseudoxanthoma elasticum: Systemic and local regulatory factors
Aberrant mineralization of connective tissues in a mouse model of pseudoxanthoma elasticum: Systemic and local regulatory factors
复制标题
DOI：
10.1038/sj.jid.5700729
复制
发表时间：
2007-06-01
影响因子：
6.5
通讯作者：
Uitto, Jouni
中科院分区：
文献类型：
--
作者：
Jiang, Qiujie;Li, Qiaoli;Uitto, Jouni
弹性假黄瘤 (PXE) 是由 ABCC6 基因突变引起的，但导致软组织矿化异常的细胞和分子事件尚不清楚。为了表征矿化过程，我们检查了 PXE 动物模型（Abcc6-/- 小鼠）作为矿化抑制剂的特定蛋白质。这些小鼠血清中的钙和磷酸盐水平正常，但Abcc6-/-血清阻止细胞培养系统中无机磷酸盐诱导的矿物质沉积的能力较差。在培养系统中添加胎球蛋白-A 可以防止矿化。 Abcc6-/- 小鼠矿化触毛中的钙 x 磷酸盐产物显着升高，这是矿化过程的早期生物标志物，与组织病理学结果一致。 Abcc6-/- 血清中胎球蛋白-A 的水平略有下降，基质-gla-蛋白 (MGP)、胎球蛋白-A 和强直蛋白 (Ank) 的阳性免疫染色以及碱性磷酸酶活性与矿化过程密切相关。原位杂交表明MGP和Ank基因在触毛中局部表达，而胎球蛋白-A在肝脏中高表达。这些数据表明，骨相关蛋白的沉积在空间上与矿化一致，并在局部和系统上积极调节这一过程。
Pseudoxanthoma elasticum (PXE) is caused by mutations in the ABCC6 gene, but the cellular and molecular events leading to aberrant mineralization of soft tissues are unknown. To characterize the mineralization process, we examined a PXE animal model, the Abcc6-/- mouse, with respect to specific proteins serving as inhibitors of mineralization. The levels of calcium and phosphate in serum of these mice were normal, but the Abcc6-/- serum had less ability to prevent the mineral deposition induced by inorganic phosphate in a cell culture system. Addition of fetuin-A to the culture system prevented the mineralization. The calcium x phosphate product was markedly elevated in the mineralized vibrissae of Abcc6-/- mice, an early biomarker of the mineralization process, consistent with histopathologic findings. Levels of fetuin-A were slightly decreased in Abcc6-/- serum, and positive immunostaining for matrix-gla-protein (MGP), fetuin-A, and ankylosis protein (Ank) as well as alkaline phosphatase activity were strongly associated with the mineralization process. In situ hybridization demonstrated that the genes for MGP and Ank were expressed locally in vibrissae, whereas fetuin-A was expressed highly in the liver. These data suggest that the deposition of the bone-associated proteins spatially coincides with mineralization and actively regulates this process locally and systemically.