Research ArticleVascular Disease

Increased activity of TNAP compensates for reduced adenosine production and promotes ectopic calcification in the genetic disease ACDC

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Science Signaling  13 Dec 2016:
Vol. 9, Issue 458, pp. ra121
DOI: 10.1126/scisignal.aaf9109

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Understanding vascular calcification

ACDC is a rare genetic vascular calcification disease caused by loss of CD73, a secreted enzyme that converts adenosine monophosphate (AMP) to adenosine. Cells from ACDC patients have a compensatory increase in the phosphatase TNAP, which primarily catalyzes the conversion of pyrophosphate to inorganic phosphate but can also convert AMP to adenosine. Jin et al. generated induced pluripotent stem cells (iPSCs) from ACDC patients. Although in culture, these cells generated adenosine from AMP, the cells had decreased amounts of pyrophosphate, which inhibits calcification. ACDC patient–derived cells showed increased activation of the mTOR pathway, which promotes calcification. When injected into mice, the ACDC patient–derived iPSCs formed calcified teratomas. Treating mice bearing these teratomas with an adenosine receptor agonist, the mTOR inhibitor rapamycin, or etidronate (a drug that is structurally similar to pyrophosphate) reduced calcification in the teratomas, suggesting multiple potential strategies for treating ectopic calcification in ACDC patients and thereby alleviating the pain and peripheral ischemia associated with the disease.

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