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The etiology of DISH is unknown and there are no specific treatments. Recent studies have suggested a role for purine metabolism in the regulation of biomineralization. Equilibrative nucleoside transporter 1 (ENT1) transfers hydrophilic nucleosides, such as adenosine, across the plasma membrane. In mice lacking ENT1, we observed the development of calcified lesions resembling DISH. By 12 months of age, ENT1\u2013\/\u2013 mice exhibited signs of spine stiffness, hind limb dysfunction, and paralysis. Micro\u2013computed tomography (\u00b5CT) revealed ectopic mineralization of paraspinal tissues in the cervical-thoracic region at 2 months of age, which extended to the lumbar and caudal regions with advancing age. Energy-dispersive X-ray microanalysis of lesions revealed a high content of calcium and phosphorus with a ratio similar to that of cortical bone. At 12 months of age, histological examination of ENT1\u2013\/\u2013 mice revealed large, 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, indicating specificity for the axial skeleton. Plasma adenosine levels were significantly greater in ENT1\u2013\/\u2013 mice than in wild-type, consistent with loss of ENT1\u2014a primary adenosine uptake pathway. There was a significant reduction in the expression of Enpp1, Ank, and Alpl in intervertebral discs from ENT1\u2013\/\u2013 mice compared to wild-type mice. Elevated plasma levels of inorganic pyrophosphate in ENT1\u2013\/\u2013 mice indicated generalized disruption of pyrophosphate homeostasis. This is the first report of a role for ENT1 in regulating the calcification of soft tissues. Moreover, ENT1\u2013\/\u2013 mice may be a useful model for investigating pathogenesis and evaluating therapeutics for the prevention of mineralization in DISH and related disorders. \u00a9 2013 American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbmr.1826","type":"journal-article","created":{"date-parts":[[2012,11,26]],"date-time":"2012-11-26T23:26:31Z","timestamp":1353972391000},"page":"1135-1149","source":"Crossref","is-referenced-by-count":89,"title":["Loss of equilibrative nucleoside transporter 1 in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis in humans"],"prefix":"10.1093","volume":"28","author":[{"given":"Sumeeta","family":"Warraich","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek 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The University of Western Ontario, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryle A","family":"S\u00e9guin","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James R","family":"Hammond","sequence":"additional","affiliation":[{"name":"Current address: JRH, Department of Pharmacology, University of Alberta, Edmonton, AB, Canada."},{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, ON, 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