Dmp1 promoter-driven diphtheria toxin receptor transgene expression directs unforeseen effects in multiple tissues

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

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Article number29
JournalInternational journal of molecular sciences
Volume18
Issue number1
DOIs
StatePublished - Jan 2017

Keywords

  • Bone
  • Diphtheria toxin receptor
  • Osteocyte

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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  • Cite this

    Al-Jazzar, A., Javaheri, B., Prideaux, M., Boyde, A., Scudamore, C. L., Cherifi, C., Hay, E., Hopkinson, M., Boyd, M., Cohen-Solal, M., Farquharson, C., & Pitsillides, A. A. (2017). Dmp1 promoter-driven diphtheria toxin receptor transgene expression directs unforeseen effects in multiple tissues. International journal of molecular sciences, 18(1), [29]. https://doi.org/10.3390/ijms18010029