Dmp1 Promoter-Driven Diphtheria Toxin Receptor Transgene Expression Directs Unforeseen Effects in Multiple Tissues.
Dmp1 Promoter-Driven Diphtheria Toxin Receptor Transgene Expression Directs Unforeseen Effects in Multiple Tissues.
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DOI：
10.3390/ijms18010029
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发表时间：
2016-12-26
影响因子：
5.6
通讯作者：
Pitsillides AA
中科院分区：
文献类型：
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作者：
Al-Jazzar A;Javaheri B;Prideaux M;Boyde A;Scudamore CL;Cherifi C;Hay E;Hopkinson M;Boyd M;Cohen-Solal M;Farquharson C;Pitsillides AA
携带牙本质基质蛋白1(Dmp1)启动子驱动的人白喉毒素受体(HDTR)转基因(TG)的小鼠最近被用于通过白喉毒素(DT)治疗实现对骨细胞的靶向消融，以确定骨细胞的功能。使用这些转基因小鼠已经断言了机械和新的旁分泌调节骨细胞的功能。为了充分探索骨细胞的作用，我们试图证实DT效应在这些转基因小鼠中的选择性。然而，我们的发现显示，与野生型(WT)小鼠相比，TG组不完全的DT诱导的骨细胞消融，普遍存在的HDTR错误表达，以及DT诱导的多个器官的组织病理学变化。通过显著调节延伸因子-2(EF-2)的磷酸化状态，在TG小鼠的许多非骨骼组织中也发现了DT作用的机制证据；这表明DT作用是直接的“脱靶”DT作用。最后，与WT对照组小鼠相比，这些转基因小鼠的健康和福利状况在接受DT治疗后迅速恶化。总之，这些数据使我们得出结论，当仅使用这些TG小鼠从实验中得出结论时，应该寻找骨细胞消融的替代模式，并谨慎行事。
Mice harbouring a dentin matrix protein 1 (Dmp1) promoter-driven human diphtheria toxin (DT) receptor (HDTR) transgene (Tg) have recently been used to attain targeted ablation of osteocytes by diphtheria toxin (DT) treatment in order to define osteocyte function. Use of these Tg mice has asserted mechano- and novel paracrine regulatory osteocyte functions. To explore osteocyte roles fully, we sought to confirm the selectivity of DT effects in these transgenic mice. However, our findings revealed incomplete DT-induced osteocyte ablation, prevalent HDTR misexpression, as well as more prominent histopathological DT-induced changes in multiple organs in Tg than in wild-type (WT) littermate mice. Mechanistic evidence for DT action, via prominent regulation of phosphorylation status of elongation factor-2 (EF-2), was also found in many non-skeletal tissues in Tg mice; indicative of direct “off-target” DT action. Finally, very rapid deterioration in health and welfare status in response to DT treatment was observed in these Tg when compared to WT control mice. Together, these data lead us to conclude that alternative models for osteocyte ablation should be sought and caution be exercised when drawing conclusions from experiments using these Tg mice alone.
影响因子：
3.2
作者：
Li C;Xie X;Wang X;Sun Y;Liu P;Chen L;Qin C
通讯作者：
Qin C