Treatment of hypophosphatemic rickets in generalized arterial calcification of infancy (GACI) without worsening of vascular calcification

Ferreira, Carlos R.; Ziegler, Shira G.; Gupta, Ashutosh; Groden, Catherine; Hsu, Kevin; Gahl, William A.

doi:10.1002/ajmg.a.37574

Cited by 28 publications

(28 citation statements)

References 11 publications

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“…Interestingly, ENPP1 knockdown related accelerated proliferation in VSMCs could not be inhibited by the addition of PP i or bisphosphonates, i.e., the synthetic analogues of PP i , indicating a mechanism that is independent of ENPP1-mediated extracellular PP i concentration. This result is in accordance with clinical studies in GACI individuals showing that treatment with bisphosphonates increases the rate of survival, but has no influence on intimal proliferation or vascular stenosis in ENPP1-deficient patients 1 , 6 , 33 . Recently, it has been shown that the treatment of Enpp1 asj/asj mice with recombinant ENPP1 elevated extracellular PP i levels and inhibited arterial calcification 21 .…”

Section: Discussionsupporting

confidence: 91%

“…Especially in recent years, different approaches for treating GACI have been intensively investigated, including early generation bisphosphonates 6 , 28 , 29 , orally administered PP i 20 and soluble recombinant ENPP1-Fc protein 21 . However, all of these studies focused on treating arterial calcification, while the most prominent complications for GACI patients are severe congestive cardiac failure, hypertension and myocardial ischemia due to myointimal proliferation and arterial stenosis 1 , 6 . In our literature survey, approximately 72% of published GACI cases display intimal hyperplasia and/or arterial stenoses.…”

Section: Discussionmentioning

confidence: 99%

“…Generalized arterial calcification of infancy (GACI, MIM #208000) is a rare autosomal recessive disorder, and the disease frequency is one in 391,000 1 . The primary characteristics of GACI include severe calcification of the media of large and medium-sized arteries, accompanied by intimal proliferation leading to arterial stenoses within the first month of life 2 .…”

Section: Introductionmentioning

confidence: 99%

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ENPP1-Fc prevents neointima formation in generalized arterial calcification of infancy through the generation of AMP

et al. 2018

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Generalized arterial calcification of infancy (GACI) is associated with widespread arterial calcification and stenoses and is caused by mutations in ENPP1. ENPP1 encodes for ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which cleaves ATP to generate inorganic pyrophosphate (PPi) and adenosine monophosphate (AMP) extracellularly. The current study was designed to define the prevalence of arterial stenoses in GACI individuals and to identify the mechanism through which ENPP1 deficiency causes intimal proliferation. Furthermore, we aimed to effectively prevent and treat neointima formation in an animal model of GACI through the systemic administration of recombinant human (rh)ENPP1-Fc protein. Based on a literature review, we report that arterial stenoses are present in at least 72.4% of GACI cases. We evaluated the effect of rhENPP1-Fc on ENPP1-silenced human vascular smooth muscle cells (VSMCs) and on induced intimal proliferation in Enpp1-deficient ttw/ttw mice treated with carotid ligation. We demonstrate that silencing ENPP1 in VSMCs resulted in a tenfold increase in proliferation relative to that of cells transfected with negative control siRNA. The addition of rhENPP1-Fc, AMP or adenosine restored the silenced ENPP1-associated proliferation. In contrast, neither PPi nor etidronate, a current off-label treatment for GACI, had an effect on VSMC proliferation. Furthermore, subcutaneous rhENPP1-Fc protein replacement was effective in preventing and treating intimal hyperplasia induced by carotid ligation in an animal model of GACI. We conclude that ENPP1 inhibits neointima formation by generating AMP. RhENPP1-Fc may serve as an approach for the effective prevention and treatment of arterial stenoses in GACI.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ENPP1-Fc prevents neointima formation in generalized arterial calcification of infancy through the generation of AMP

et al. 2018

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“…However, subjects 1 to 4 showed no signs of rachitic dental manifestations. Subject 5 presented unusual cusp patterns and a history of extensive sealant application, as noted previously (Ferreira et al 2016). While these observations are consistent with very mild enamel effects, in isolation they are not strong evidence of rachitic teeth.…”

Section: Additional Dental Manifestations Of Gacisupporting

confidence: 70%

Hypercementosis Associated with ENPP1 Mutations and GACI

Thumbigere‐Math

Alqadi

Chalmers³

et al. 2017

J Dent Res

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Mineralization of bones and teeth is tightly regulated by levels of extracellular inorganic phosphate (P) and pyrophosphate (PP). Three regulators that control pericellular concentrations of P and PP include tissue-nonspecific alkaline phosphatase (TNAP), progressive ankylosis protein (ANK), and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). Inactivation of these factors results in mineralization disorders affecting teeth and their supporting structures. This study for the first time analyzed the effect of decreased PP on dental development in individuals with generalized arterial calcification of infancy (GACI) due to loss-of-function mutations in the ENPP1 gene. Four of the 5 subjects reported a history of infraocclusion, overretained primary teeth, ankylosis, and/or slow orthodontic tooth movement, suggesting altered mineral metabolism contributing to disrupted tooth movement and exfoliation. All subjects had radiographic evidence of unusually protruding cervical root morphology in primary and/or secondary dentitions. High-resolution micro-computed tomography (micro-CT) analyses of extracted primary teeth from 3 GACI subjects revealed 4-fold increased cervical cementum thickness ( P = 0.00007) and a 23% increase in cementum density ( P = 0.009) compared to age-matched healthy control teeth. There were no differences in enamel and dentin densities between GACI and control teeth. Histology revealed dramatically expanded cervical cementum in GACI teeth, including cementocyte-like cells and unusual patterns of cementum resorption and repair. Micro-CT analysis of Enpp1 mutant mouse molars revealed 4-fold increased acellular cementum thickness ( P = 0.002) and 5-fold increased cementum volume ( P = 0.002), with no changes in enamel or dentin. Immunohistochemistry identified elevated ENPP1 expression in cementoblasts of human and mouse control teeth. Collectively, these findings reveal a novel dental phenotype in GACI and identify ENPP1 genetic mutations associated with hypercementosis. The sensitivity of cementum to reduced PP levels in both human and mouse teeth establishes this as a well-conserved and fundamental biological process directing cementogenesis across species (ClinicalTrials.gov NCT00369421).

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“…48,49 Indeed, both decreased and increased bone turnover are shown to accelerate VC process. 50,51 In this regard, decreased mineralization in the bone of uremic PiT-2 HET mice fed a high P diet might have contributed to the enhanced VC in our study. However, it still remains unclear which bone cells were affected by PiT-2 deficiency and how PiT-2 deficiency altered bone metabolism.…”

Section: Discussionmentioning

confidence: 65%

PiT-2, a type III sodium-dependent phosphate transporter, protects against vascular calcification in mice with chronic kidney disease fed a high-phosphate diet

Yamada

Leaf

Chia

et al. 2018

Kidney International

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PiT-2, a type III sodium-dependent phosphate transporter, is a causative gene for the brain arteriolar calcification in people with familial basal ganglion calcification. Here we examined the effect of PiT-2 haploinsufficiency on vascular calcification in uremic mice using wild-type and global PiT-2 heterozygous knockout mice. PiT-2 haploinsufficiency enhanced the development of vascular calcification in mice with chronic kidney disease fed a high-phosphate diet. No differences were observed in the serum mineral biomarkers and kidney function between the wild-type and PiT-2 heterozygous knockout groups. Micro computed tomography analyses of femurs showed that haploinsufficiency of PiT-2 decreased trabecular bone mineral density in uremia. In vitro, sodium-dependent phosphate uptake was decreased in cultured vascular smooth muscle cells isolated from PiT-2 heterozygous knockout mice compared with those from wild-type mice. PiT-2 haploinsufficiency increased phosphate-induced calcification of cultured vascular smooth muscle cells compared to the wild-type. Furthermore, compared to wild-type vascular smooth muscle cells, PiT-2 deficient vascular smooth muscle cells had lower osteoprotegerin levels and increased matrix calcification, which was attenuated by osteoprotegerin supplementation. Thus, PiT-2 in vascular smooth muscle cells protects against phosphate-induced vascular calcification and may be a therapeutic target in the chronic kidney disease population.

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Treatment of hypophosphatemic rickets in generalized arterial calcification of infancy (GACI) without worsening of vascular calcification

Cited by 28 publications

References 11 publications

ENPP1-Fc prevents neointima formation in generalized arterial calcification of infancy through the generation of AMP

ENPP1-Fc prevents neointima formation in generalized arterial calcification of infancy through the generation of AMP

Hypercementosis Associated with ENPP1 Mutations and GACI

PiT-2, a type III sodium-dependent phosphate transporter, protects against vascular calcification in mice with chronic kidney disease fed a high-phosphate diet

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