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Dmp1 Promoter-Driven Diphtheria Toxin Receptor Transgene Expression Directs Unforeseen Effects in Multiple Tissues

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  • Ahmed Al-Jazzar
  • Behzad Javaheri
  • Matt Prideaux
  • Alan Boyde
  • Cheryl Scudamore
  • Chahrazad Cherifi
  • Eric Hay
  • Mark Hopkinson
  • Michael Boyd
  • Martine Cohen-Solal
  • Colin Farquharson
  • Andrew Pitsillides

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    Rights statement: © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).

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    Licence: Creative Commons: Attribution (CC-BY)

Original languageEnglish
Article number29
Number of pages18
JournalInternational Journal of Molecular Sciences
Volume18
Issue number1 Sp Issue
Early online date26 Dec 2016
DOIs
Publication statusPublished - 2017

Abstract

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.

    Research areas

  • osteocyte, diphtheria toxin receptor, bone

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