Juxta-articular joint-capsule mineralization in CD73 deficient mice: Similarities to patients with<i>NT5E</i>mutations

Li, Qiaoli; Price, Thea P.; Sundberg, John P.; Uitto, Jouni

doi:10.4161/15384101.2014.943567

Cited by 47 publications

(29 citation statements)

References 28 publications

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“…The rats, representing three mutant lines, Lines 2, 3, and 4, were subjected to complete necropsy to examine tissue mineralization in a systematic manner, as described previously (Berndt et al , 2013; Li et al , 2013; Li et al , 2014a; Li et al , 2014b). Histopathological examination of homozygous rats from the three mutant lines on standard rodent diet demonstrated extensive mineralization in the dermal sheath of vibrissae as well as in a number of internal organs when examined by hematoxylin and eosin (H&E) or Alizarin red stains (Fig.…”

Section: Resultsmentioning

confidence: 99%

Abcc6 Knockout Rat Model Highlights the Role of Liver in PPi Homeostasis in Pseudoxanthoma Elasticum

Kingman

Wetering

et al. 2017

Journal of Investigative Dermatology

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Pseudoxanthoma elasticum (PXE), a heritable ectopic mineralization disorder, is caused by mutations in the ABCC6 gene primarily expressed in the liver and the kidneys. The fundamental question on pathogenesis of PXE, whether lack of ABCC6 expression in liver or kidney is the primary site of molecular pathology in peripheral tissues, has not been addressed. We generated a series of Abcc6−/− rats as models of PXE depicting ectopic mineralization in the skin, eyes, and the arterial blood vessels. Plasma PPi level was reduced (<30%) in the Abcc6−/− rats leading to lowered PPi/Pi plasma ratio. In situ liver and kidney perfusions were performed to determine the relative contribution of these organs to PPi levels in circulation. PPi levels in the perfusates both in the liver and kidney of Abcc6−/− rats were significantly reduced, but the PPi levels in the liver perfusates of wild type rats were 10-fold higher than that in the kidney perfusates. These observations suggest a critical role of hepatic ABCC6 in contributing to plasma PPi levels, identifying liver as a target of molecular correction to counteract ectopic mineralization in PXE.

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Section: Resultsmentioning

confidence: 99%

Abcc6 Knockout Rat Model Highlights the Role of Liver in PPi Homeostasis in Pseudoxanthoma Elasticum

Kingman

Wetering

et al. 2017

Journal of Investigative Dermatology

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“…Indeed, patients with ACDC and CD73-deficient mice develop dystrophic calcification, [84, 85]. However, this hypothesis is weakened by the lack of adenosine transport by ABCC6 in in vitro experiments [86].…”

Section: Etiologymentioning

confidence: 99%

Pseudoxanthoma elasticum

Germain

2017

Orphanet J Rare Dis

137

147

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Pseudoxanthoma elasticum (PXE) is a genetic metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. The lack of functional ABCC6 protein leads to ectopic mineralization that is most apparent in the elastic tissues of the skin, eyes and blood vessels. The clinical prevalence of PXE has been estimated at between 1 per 100,000 and 1 per 25,000, with slight female predominance. The first clinical sign of PXE is almost always small yellow papules on the nape and sides of the neck and in flexural areas. The papules coalesce, and the skin becomes loose and wrinkled. The mid-dermal elastic fibers are short, fragmented, clumped and calcified. Dystrophic calcification of Bruch’s membrane, revealed by angioid streaks, may trigger choroidal neovascularization and, ultimately, loss of central vision and blindness in late-stage disease. Lesions in small and medium-sized artery walls may result in intermittent claudication and peripheral artery disease. Cardiac complications (myocardial infarction, angina pectoris) are thought to be relatively rare but merit thorough investigation. Ischemic strokes have been reported. PXE is a metabolic disease in which circulating levels of an anti-mineralization factor are low. There is good evidence to suggest that the factor is inorganic pyrophosphate (PPi), and that the circulating low levels of PPi and decreased PPi/Pi ratio result from the lack of ATP release by hepatocytes harboring the mutant ABCC6 protein. However, the substrate(s) bound, transported or modulated by the ABCC6 protein remain unknown. More than 300 sequence variants of the ABCC6 gene have been identified. There is no cure for PXE; the main symptomatic treatments are vascular endothelial growth factor inhibitor therapy (for ophthalmic manifestations), lifestyle, lipid-lowering and dietary measures (for reducing vascular risk factors), and vascular surgery (for severe cardiovascular manifestations). Future treatment options may include gene therapy/editing and pharmacologic chaperone therapy.

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“…Mice with CD73 deficiency, however, cannot be used to study the ACDC disease mechanism because they do not mimic the human vascular phenotype (14). Therefore, we have established patient-specific in vitro and in vivo disease models using induced pluripotent stem cell (iPSC) technology to determine the mechanisms by which CD73 deficiency leads to VC in ACDC patients.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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 rapamycin, or the bisphosphonate etidronate reduced calcification. These results show that an increase of TNAP activity in ACDC contributes to ectopic calcification by disrupting the extracellular balance of PPi and Pi and identify potential therapeutic targets for ACDC.

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Juxta-articular joint-capsule mineralization in CD73 deficient mice: Similarities to patients withNT5Emutations

Cited by 47 publications

References 28 publications

Abcc6 Knockout Rat Model Highlights the Role of Liver in PPi Homeostasis in Pseudoxanthoma Elasticum

Abcc6 Knockout Rat Model Highlights the Role of Liver in PPi Homeostasis in Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum

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

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