Transgenic expression of Dspp partially rescued the long bone defects of Dmp1-null mice.
Transgenic expression of Dspp partially rescued the long bone defects of Dmp1-null mice.
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DOI：
10.1016/j.matbio.2015.12.001
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发表时间：
2016-05
期刊：
影响因子：
--
通讯作者：
Qin C
中科院分区：
文献类型：
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作者：
Jani PH;Gibson MP;Liu C;Zhang H;Wang X;Lu Y;Qin C
牙本质基质蛋白1（Dentin matrix protein 1，DMP 1）和牙本质涎磷蛋白（dentin sialophosphoprotein，DSPP）属于小整合素结合配体N-连接糖蛋白（Small Integrin Binding Ligand N-linked Glycoprotein，SIBLING）家族。除了所有SIBLING成员共有的特征之外，DMP 1和DSPP在化学结构、蛋白水解活化和组织定位方面具有一些独特的相似性。DMP 1的突变或缺失可导致常染色体隐性低磷血症性佝偻病沿着牙齿缺陷; DSPP突变或其缺失与牙本质形成相关。虽然DMP 1在骨生成中的作用和功能机制已被广泛研究，但DSPP在长骨中的作用和功能机制仅在有限程度上进行了研究。我们小组以前的研究表明，Dspp的转基因表达完全挽救了Dmp 1-null（Dmp 1 −/−）小鼠的牙本质缺陷。在这项研究中，我们通过分析Dmp 1 −/−小鼠（称为“Dmp 1 −/−;Dspp-Tg小鼠”）长骨的形成和矿化来评估转基因Dspp对骨生成的影响，Dmp 1 −/−小鼠表达由3.6 kb大鼠Col 1a 1启动子驱动的编码全长DSPP的转基因。我们对不同年龄的Dmp 1 −/−;Dspp-Tg小鼠的长骨进行了表征，并将其与Dmp 1 −/−和Dmp 1 +/−（正常对照）小鼠的长骨进行了比较。我们的分析表明，与Dmp 1 −/−小鼠相比，Dmp 1 −/−;Dspp-Tg小鼠的长骨皮质骨厚度、骨体积和矿物质密度沿着显著增加，骨小梁厚度显著恢复。与Dmp 1 −/−小鼠相比，Dmp 1 −/−;Dspp-Tg小鼠的长骨经历了类骨质数量的急剧减少，胶原纤维网络的显着改善，以及陷窝小管系统的更好组织。在Dmp 1 −/−小鼠中，双糖蛋白聚糖、骨唾液酸蛋白和骨桥蛋白水平的升高也被Dspp的转基因表达显著纠正。这些发现表明DSPP和DMP 1可能在骨基质的复杂环境中协同发挥作用。
Dentin matrix protein 1 (DMP1) and dentin sialophosphoprotein (DSPP) belong to the Small Integrin-Binding Ligand N-linked Glycoprotein (SIBLING) family. In addition to the features common to all SIBLING members, DMP1 and DSPP share several unique similarities in chemical structure, proteolytic activation and tissue localization. Mutations in, or deletion of DMP1, cause autosomal recessive hypophosphatemic rickets along with dental defects; DSPP mutations or its ablation are associated with dentinogenesis imperfecta. While the roles and functional mechanisms of DMP1 in osteogenesis have been extensively studied, those of DSPP in long bones have been studied only to a limited extent. Previous studies by our group revealed that transgenic expression of Dspp completely rescued the dentin defects of Dmp1-null (Dmp1−/−) mice. In this investigation, we assessed the effects of transgenic Dspp on osteogenesis by analyzing the formation and mineralization of the long bones in Dmp1−/− mice that expresses a transgene encoding full-length DSPP driven by a 3.6-kb rat Col1a1 promoter (referred as “Dmp1−/−;Dspp-Tg mice”). We characterized the long bones of the Dmp1−/−;Dspp-Tg mice at different ages and compared them with those from Dmp1−/− and Dmp1+/− (normal control) mice. Our analyses showed that the long bones of Dmp1−/−;Dspp-Tg mice had a significant increase in cortical bone thickness, bone volume and mineral density along with a remarkable restoration of trabecular thickness compared to those of the Dmp1−/− mice. The long bones of Dmp1−/−;Dspp-Tg mice underwent a dramatic reduction in the amount of osteoid, significant improvement of the collagen fibrillar network, and better organization of the lacunocanalicular system, compared to the Dmp1−/− mice. The elevated levels of biglycan, bone sialoprotein and osteopontin in Dmp1−/− mice were also noticeably corrected by the transgenic expression of Dspp. These findings suggest that DSPP and DMP1 may function synergistically within the complex milieus of bone matrices.