<i>NT5E</i>Mutations and Arterial Calcifications

Hilaire, Cynthia St.; Ziegler, Shira G.; Markello, Thomas C.; Brusco, Alfredo; Groden, Catherine; Gill, Fred A.; Carlson-Donohoe, Hannah; Lederman, Robert J.; Chen, Marcus Y; Yang, Dan; Siegenthaler, Michael; Arduino, Carlo; Mancini, Cecilia; Freudenthal, Bernard; Stanescu, Horia; Zdebik, Anselm A.; Chaganti, R. Krishna; Nussbaum, Robert L.; Kleta, Robert; Gahl, William A.; Boehm, Manfred

doi:10.1056/nejmoa0912923

Cited by 406 publications

(327 citation statements)

References 28 publications

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“…Interestingly, a phenotype in humans with CD73 deficiency has also been identified. These individuals have premature peripheral arterial calcifications and are affected by debilitating claudication 55. The findings illustrate a crucial role of CD73‐mediated adenosine production in regulating vascular inflammation.…”

Section: Discussionmentioning

confidence: 88%

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Shin

Wang

Zemskova

et al. 2018

JAHA

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BackgroundDuring myocardial ischemia/reperfusion (MI/R) injury, there is extensive release of immunogenic metabolites that activate cells of the innate immune system. These include ATP and AMP, which upregulate chemotaxis, migration, and effector function of early infiltrating inflammatory cells. These cells subsequently drive further tissue devitalization. Mesenchymal stromal cells (MSCs) are a potential treatment modality for MI/R because of their powerful anti‐inflammatory capabilities; however, the manner in which they regulate the acute inflammatory milieu requires further elucidation. CD73, an ecto‐5′‐nucleotidase, may be critical in regulating inflammation by converting pro‐inflammatory AMP to anti‐inflammatory adenosine. We hypothesized that MSC‐mediated conversion of AMP into adenosine reduces inflammation in early MI/R, favoring a micro‐environment that attenuates excessive innate immune cell activation and facilitates earlier cardiac recovery.Methods and ResultsAdult rats were subjected to 30 minutes of MI/R injury. MSCs were encapsulated within a hydrogel vehicle and implanted onto the myocardium. A subset of MSCs were pretreated with the CD73 inhibitor, α,β‐methylene adenosine diphosphate, before implantation. Using liquid chromatography/mass spectrometry, we found that MSCs increase myocardial adenosine availability following injury via CD73 activity. MSCs also reduce innate immune cell infiltration as measured by flow cytometry, and hydrogen peroxide formation as measured by Amplex Red assay. These effects were dependent on MSC‐mediated CD73 activity. Finally, through echocardiography we found that CD73 activity on MSCs was critical to optimal protection of cardiac function following MI/R injury.Conclusions MSC‐mediated conversion of AMP to adenosine by CD73 exerts a powerful anti‐inflammatory effect critical for cardiac recovery following MI/R injury.

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Section: Discussionmentioning

confidence: 88%

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Shin

Wang

Zemskova

et al. 2018

JAHA

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“…Thus, it is logical to assume that CD73 would be an essential component of plaque development and maturation. Impairment of CD73 has been associated to the early development of PAD in the form of extensive calcification [5]. Recently, we studied the general level of CD73 activity in a cohort of patients with PAD but found no impairment of CD73.…”

Section: Discussionmentioning

confidence: 95%

“…Impaired CD73-derived (ecto-5′-nucleotidase) adenosine production has been shown to contribute to the development of atherosclerosis both in mice and men [2][3][4] and also leading to the calcification of lower limb arteries in man [5]. Therefore, we recently explored CD73 activity in blood samples of a wellestablished cohort of patients with symptomatic lower limb atherosclerosis, which is more commonly referred to as peripheral artery disease (PAD) [6].…”

Section: Introductionmentioning

confidence: 99%

Regulation of CD73 in the development of lower limb atherosclerosis

Jalkanen

Hollmén

Jalkanen

et al. 2016

Purinergic Signalling

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Atherosclerosis is an inflammatory process of the arterial wall. CD73 (also known as ecto-5′-nucleotidase) is a key regulator of cell signaling in response to inflammation and hypoxia, and may be important in the development of atherosclerosis. Recently, we have shown that high CD73 activity can be detected in the serum of patients with peripheral arterial disease (PAD). Using this same PAD patient cohort of 226 subjects with 38 femoral artery samples obtained during surgical endarcterectomy and control artery samples taken during autopsy, we explored the association of serum CD73 activity with overall atherosclerotic burden and the expression of CD73 in mature and developing plaques. Interestingly, we found that CD73 activity had a tendency to increase along with more severe presentation of PAD (from 249 nmol/mL/h in moderate disease to 332 nmol/mL/h in severe disease; P = 0.013) and that CD73 expression is elevated in the vasa vasorum of developing plaques, but completely lost in mature occlusive plaques removed during endarcterectomy (P < 0.001). The current findings implicate that as a result of shedding and loss of CD73 from the arterial wall, CD73 activity is elevated in the serum of patients with widespread atherosclerosis. These findings highlight the importance of a better understanding of the local role of CD73 in the development and maturation of arterial atherosclerotic plaques in man.

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“…(18) Recent advances point to a critical role for purine metabolism in the regulation of biomineralization in diseases associated with either insufficient or ectopic mineralization. (25)(26)(27)(28)(29)(30) For example, mutations in the gene encoding ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) have been associated with hypermineralization disorders. (25,26) Moreover, a recent study has linked ectopic arterial and joint calcifications with loss of ecto-5 0 -nucleotidase (5 0 NTD) function leading to decreased levels of extracellular adenosine.…”

Section: J Jbmrmentioning

confidence: 99%

“…(25,26) Moreover, a recent study has linked ectopic arterial and joint calcifications with loss of ecto-5 0 -nucleotidase (5 0 NTD) function leading to decreased levels of extracellular adenosine. (27) To further explore the role of purine metabolism in the regulation of biomineralization, we examined the phenotype of the mouse lacking the gene encoding the nucleoside transporter ENT1. ENT1 (equilibrative nucleoside transporter 1 or solute carrier family 29 member 1, encoded by the Slc29a1 locus) is the predominant nucleoside transporter expressed in mammalian cells.…”

Section: J Jbmrmentioning

confidence: 99%

Loss of equilibrative nucleoside transporter 1 in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis in humans

Warraich

Bone

Quinonez

et al. 2012

Journal of Bone and Mineral Research

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Diffuse idiopathic skeletal hyperostosis (DISH) is a noninflammatory spondyloarthropathy, characterized by ectopic calcification of spinal tissues. Symptoms include spine pain and stiffness, and in severe cases dysphagia and spinal cord compression. 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 -/-mice exhibited signs of spine stiffness, hind limb dysfunction, and paralysis. Micro-computed tomography (mCT) 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 -/-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 -/-mice than in wild-type, consistent with loss of ENT1-a primary adenosine uptake pathway. There was a significant reduction in the expression of Enpp1, Ank, and Alpl in intervertebral discs from ENT1 -/-mice compared to wild-type mice. Elevated plasma levels of inorganic pyrophosphate in ENT1 -/-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 -/-mice may be a useful model for investigating pathogenesis and evaluating therapeutics for the prevention of mineralization in DISH and related disorders. ß

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NT5EMutations and Arterial Calcifications

Cited by 406 publications

References 28 publications

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Regulation of CD73 in the development of lower limb atherosclerosis

Loss of equilibrative nucleoside transporter 1 in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis in humans

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