Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology

Supervisor

Dr. James Hammond and Dr. Cheryle Séguin

Abstract

Equilibrative nucleoside transporter 1 (ENT1) regulates the bi-directional transfer of hydrophilic nucleosides, such as adenosine, across the plasma membrane. Mice lacking ENT1 developed calcified lesions resembling diffuse idiopathic skeletal hyperostosis (DISH) in humans. By 12 months of age, ENT1-/- mice exhibit spine stiffness, hind limb dysfunction, and paralysis. Histological examination of ENT1-/- mice revealed irregular accumulations of eosinophilic material in paraspinal ligaments and entheses, intervertebral discs, and sternocostal articulations. There was no evidence of mineralization in appendicular joints or blood vessels. Analysis of intervertebral disc tissues of 6 month old ENT1-/- and wild-type mice revealed reduced expression of mineralization inhibitors, including matrix gla protein (Mgp), ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1), progressive ankylosis (Ank), and osteopontin (Spp1). The expression of these genes was not altered in tissues which do not exhibit ectopic mineralization. Thus, a reduction of proteins that normally prevent soft tissue mineralization may induce the ectopic calcification of spinal tissues observed in ENT1-/- mice.


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