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

作者：Hui Zi Jin, Cynthia St. Hilaire, Yuting Huang, Dan Yang, Natalia I. Dmitrieva, Alejandra Negro, Robin Schwartzbeck, Yangtengyu Liu, Zhen Yu, Avram D. Walts, Jean-Michel Davaine, Duck‐Yeon Lee, Danielle Donahue, Kevin S. Hsu, Jessica Chen, Tao Cheng, William Allen Gahl, Guibin Chen, Manfred Boehm · 发表于：Science Signaling · 年份：2016 · DOI：10.1126/scisignal.aaf9109 · 被引用次数：87 · 研究领域：Alkaline Phosphatase Research Studies、Connective tissue disorders research、Dermatological and Skeletal Disorders

ACDC (arterial calcification due to deficiency of CD73) is an autosomal recessive disease resulting from loss-of-function mutations in NT5E, which encodes CD73, a 5'-ectonucleotidase that converts extracellular adenosine monophosphate to adenosine. ACDC patients display progressive calcification of lower extremity arteries, causing limb ischemia. Tissue-nonspecific alkaline phosphatase (TNAP), which converts pyrophosphate (PPi) to inorganic phosphate (Pi), and extracellular purine metabolism play important roles in other inherited forms of vascular calcification. Compared to cells from healthy subjects, induced pluripotent stem cell-derived mesenchymal stromal cells (iMSCs) from ACDC patients displayed accelerated calcification and increased TNAP activity when cultured under conditions that promote osteogenesis. TNAP activity generated adenosine in iMSCs derived from ACDC patients but not in iMSCs from control subjects, which have CD73. In response to osteogenic stimulation, ACDC patient-derived iMSCs had decreased amounts of the TNAP substrate PPi, an inhibitor of extracellular matrix calcification, and exhibited increased activation of AKT, mechanistic target of rapamycin (mTOR), and the 70-kDa ribosomal protein S6 kinase (p70S6K), a pathway that promotes calcification. In vivo, teratomas derived from ACDC patient cells showed extensive calcification and increased TNAP activity. Treating mice bearing these teratomas with an A2b adenosine receptor agonist, the mTOR inhibitor...