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Int. J. Mol. Sci. 2017, 18(1), 29; doi:10.3390/ijms18010029

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

1
Skeletal Biology Group, Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK
2
Orthopaedics & Trauma, University of Adelaide, Adelaide, SA 5005, Australia
3
Dental Physical Sciences, Institute of Dentistry, Queen Mary University of London, Mile End Campus, London E1 4NS, UK
4
Mary Lyon Centre, MRC Harwell, Science & Innovation Campus, Oxfordshire OX11 0RD, UK
5
Inserm U1132 & Université Sorbonne Paris Cité-Diderot, Rheumatology, Hôpital Lariboisière, Paris 75010, France
6
Roslin Institute, University of Edinburgh, Division of Developmental Biology, Easter Bush, Midlothian EH25 9RG, UK
*
Author to whom correspondence should be addressed.
Academic Editor: Cory J. Xian
Received: 2 November 2016 / Revised: 13 December 2016 / Accepted: 15 December 2016 / Published: 26 December 2016
(This article belongs to the Special Issue Advances in Bone and Cartilage Research)
View Full-Text   |   Download PDF [19172 KB, uploaded 26 December 2016]   |  

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. View Full-Text
Keywords: osteocyte; diphtheria toxin receptor; bone osteocyte; diphtheria toxin receptor; bone
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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. Dmp1 Promoter-Driven Diphtheria Toxin Receptor Transgene Expression Directs Unforeseen Effects in Multiple Tissues. Int. J. Mol. Sci. 2017, 18, 29.

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