ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy

Albright, Ronald A.; Stabach, Paul R.; Cao, Wenxiang; Kavanagh, Dillon; Mullen, Isabelle; Braddock, Alexander; Covo, Mariel S.; Tehan, Martin; Yang, Guangxiao; Cheng, Zhiliang; Bouchard, Keith; Yu, Zhao-Xue; Thorn, Stephanie; Wang, Xiangning; Folta‐Stogniew, Ewa; Negrete, Alejandro; Sinusas, Albert J.; Shiloach, Joseph; Zubal, George; Madri, Joseph A.; Cruz, Enrique M. De La; Braddock, Demetrios T.

doi:10.1038/ncomms10006

Cited by 106 publications

(115 citation statements)

References 36 publications

Supporting

Mentioning

113

Contrasting

Order By: Relevance

“…Patients with biallelic ABCC6 mutations associated with GACI type 2 exhibit plasma PPi levels of approximately 0.5 μM, and assays performed on a limited number of infants with biallelic ENPP1 deficiency and extensive vascular calcifications (overt symptoms of GACI type 1) returned levels between 70 and 250 nM (KZ and DTB, unpublished observations). Finally, PPi assays performed on ENPP 1‐deficient mice in our laboratory routinely return levels between 250 and 500 nM . However, plasma PPi has not been systematically studied in asymptomatic patients, and therefore normal levels of plasma PPi are less well established.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Biochemical Phenotypes in a Family With ENPP1 Mutations

Kotwal

Ferrer

Kumar

et al. 2019

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Inactivating mutations of the ENPP1 gene are associated with generalized arterial calcification of infancy (GACI) and less often autosomal‐recessive hypophosphatemic rickets type 2 (ARHR2). We aimed to investigate the spectrum of phenotypes in a family with monoallelic and biallelic mutations of ENPP1 after identification through whole exome sequencing of a 54‐year‐old female with biallelic mutation of ENPP1, c.323G > T; p.Cys108Phe and c.1441C > T; p.Arg481Trp. Including the proband, 2 subjects had biallelic mutations, 5 had monoallelic mutations, and 2 had no mutation of ENPP1. The maternal mutation, a known pathogenic variant associated with GACI, was found in 3 subjects with monoallelic mutations, while the paternal mutation, which was not previously reported, was present in 2 subjects with monoallelic mutations. Both subjects with biallelic mutations had bowing of bilateral femurs, periarticular mineral deposition, normocalcemic primary hyperparathyroidism with multigland parathyroidectomy, increased carotid intima‐media thickness, and enthesopathy was also noted in one subject. Intact FGF23 was elevated in both subjects with biallelic mutations, while C‐terminal FGF23 was only elevated in one and PPi was reduced in one. Subjects with monoallelic mutations did not have periarticular calcifications or bone deformities. To conclude, patients with biallelic GACI causing mutations can survive well into adulthood, and despite the same biallelic ENPP1 pathogenic variants, clinical and biochemical manifestations can significantly differ, and include enthesopathy and primary hyperparathyroidism, which have not been previously described. Although carriers of monoallelic ENPP1 variants appear unaffected by classic disease manifestations, there may be subtle biochemical and clinical findings that warrant further investigation. © 2019 American Society for Bone and Mineral Research.

show abstract

Section: Discussionmentioning

confidence: 99%

Clinical and Biochemical Phenotypes in a Family With ENPP1 Mutations

Kotwal

Ferrer

Kumar

et al. 2019

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

show abstract

“…Enpp1 -/-VSMCs also display higher expression of chondrogenic, osteoblastic and osteocytic markers [88]. Furthermore, a recently published study has shown that subcutaneous administration of an NPP1 fusion protein prevents vascular calcification in Enpp1 asj mice [89]. In vitro studies have additionally shown that, by hydrolysing released ATP, NPP1 is a key source of pyrophosphate in VSMC cultures [20,90].…”

Section: Pyrophosphate and Vascular Calcificationmentioning

confidence: 99%

Pyrophosphate: a key inhibitor of mineralisation

Orriss

Arnett

Russell

2016

Current Opinion in Pharmacology

139

105

View full text Add to dashboard Cite

“…Murine models of Enpp1 deficiency exhibit the essential characteristics of human GACI, including arterial calcifications, neointimal hyperplasia, cardiac dysfunction, and myocardial infarctions . However, in contrast to the rickets present in human ARHR2, the skeletal phenotype present in Enpp1‐deficient mice is reported to be osteopenic/osteoporotic .…”

Section: Introductionmentioning

confidence: 99%

Human Heterozygous ENPP1 Deficiency Is Associated With Early Onset Osteoporosis, a Phenotype Recapitulated in a Mouse Model of Enpp1 Deficiency

Oheim

Zimmerman

Maulding

et al. 2019

Journal of Bone and Mineral Research

Self Cite

View full text Add to dashboard Cite

Biallelic ENPP1 deficiency in humans induces generalized arterial calcification of infancy (GACI) and/or autosomal recessive hypophosphatemic rickets type 2 (ARHR2). The latter is characterized by markedly increased circulating FGF23 levels and renal phosphate wasting, but aberrant skeletal manifestations associated with heterozygous ENPP1 deficiency are unknown. Here, we report three adult men with early onset osteoporosis who presented with fractures in the thoracic spine and/or left radius, mildly elevated circulating FGF23, and hypophosphatemia. Total hip bone mineral density scans demonstrated osteoporosis (Z‐score < −2.5) and HRpQCT demonstrated microarchitectural defects in trabecular and cortical bone. Next‐generation sequencing revealed heterozygous loss‐of‐function mutations in ENPP1 previously observed as biallelic mutations in infants with GACI. In addition, we present bone mass and structure data as well as plasma pyrophosphate (PPi) data of two siblings suffering from ARHR2 in comparison to their heterozygous and wild‐type family members indicative of an ENPP1 gene dose effect. The skeletal phenotype in murine Enpp1 deficiency yielded nearly identical findings. Ten‐week‐old male Enpp1 asj/asj mice exhibited mild elevations in plasma FGF23 and hypophosphatemia, and micro‐CT analysis revealed microarchitectural defects in trabecular and cortical bone of similar magnitude to HRpQCT defects observed in humans. Histomorphometry revealed mild osteomalacia and osteopenia at both 10 and 23 weeks. The biomechanical relevance of these findings was demonstrated by increased bone fragility and ductility in Enpp1 asj/asj mice. In summary, ENPP1 exerts a gene dose effect such that humans with heterozygous ENPP1 deficiency exhibit intermediate levels of plasma analytes associated with bone mineralization disturbance resulting in early onset osteoporosis. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

show abstract

ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy

Cited by 106 publications

References 36 publications

Clinical and Biochemical Phenotypes in a Family With ENPP1 Mutations

Clinical and Biochemical Phenotypes in a Family With ENPP1 Mutations

Pyrophosphate: a key inhibitor of mineralisation

Human Heterozygous ENPP1 Deficiency Is Associated With Early Onset Osteoporosis, a Phenotype Recapitulated in a Mouse Model of Enpp1 Deficiency

Contact Info

Product

Resources

About