Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Dr. Cheryle Séguin and Dr. Jeffrey Dixon

Abstract

Equilibrative nucleoside transporter 1 (ENT1) transfers adenosine across plasma membranes. Mice lacking ENT1 (ENT1-/-) develop pathological calcification of spinal tissues resembling diffuse idiopathic skeletal hyperostosis (DISH) in humans. Our goal was to investigate the mechanism underlying ectopic mineralization in ENT1-/- mice. We detected aberrant alkaline phosphatase (ALP, promoter of mineralization) activity in the annulus fibrosus (AF) of ENT1-/- mice. In vitro, AF cells from ENT1-/- mice exhibited greater ALP activity than cells from wild-type (WT) mice. Inhibition of ENT1 in the presence of extracellular adenosine modeled in WT cells the phenotype of ENT1-/- cells. We also characterized differences in the AF cell phenotype between WT and ENT1-/- mice using transcriptome analysis, revealing the association between activation of cell cycle and B cells with the induction of mineralization. In summary, both cell-autonomous and systemic mechanisms contribute to ectopic mineralization in ENT1-/- mice, possibly through alterations in ALP distribution and activity.


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