Inorganic Pyrophosphate Deficiency Syndromes and Potential Treatments for Pathologic Tissue Calcification

Ralph, Douglas; Wetering, Koen van de; Uitto, Jouni; Li, Qiaoli

doi:10.1016/j.ajpath.2022.01.012

Cited by 33 publications

(31 citation statements)

References 51 publications

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“…ABCC6 and ENPP1 encode proteins that are required for the generation of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification [ 1 ], and pathogenic variants in both genes have been associated with syndromes of ectopic calcification [ 2 ]. Biallelic inactivating variants in ENPP1 or ABCC6 cause generalized arterial calcification of infancy type 1 (OMIM 208000) and type 2 (OMIM 614473), respectively, rare autosomal recessive disorders that are nearly indistinguishable and often diagnosed by prenatal vascular calcification [ 3 – 5 ].…”

Section: Introductionmentioning

confidence: 99%

ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification

et al. 2022

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Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are clinically distinct genetic entities of ectopic calcification associated with differentially reduced circulating levels of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification. Variants in ENPP1, the gene mutated in GACI, have not been associated with classic PXE. Here we report the clinical, laboratory, and molecular evaluations of ten GACI and two PXE patients from five and two unrelated families registered in GACI Global and PXE International databases, respectively. All patients were found to carry biallelic variants in ENPP1. Among ten ENPP1 variants, one homozygous variant demonstrated uniparental disomy inheritance. Functional assessment of five previously unreported ENPP1 variants suggested pathogenicity. The two PXE patients, currently 57 and 27 years of age, had diagnostic features of PXE and had not manifested the GACI phenotype. The similarly reduced PPi plasma concentrations in the PXE and GACI patients in our study correlate poorly with their disease severity. This study demonstrates that in addition to GACI, ENPP1 variants can cause classic PXE, expanding the clinical and genetic heterogeneity of heritable ectopic calcification disorders. Furthermore, the results challenge the current prevailing concept that plasma PPi is the only factor governing the severity of ectopic calcification.

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Section: Introductionmentioning

confidence: 99%

ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification

et al. 2022

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“…In fact, reduced PPi plasma levels have been reported in Abcc6 knock‐out mice and rats as well as in patients with PXE 8,18,19 . Since plasma PPi levels are reduced in both PXE and GACI, albeit to different extents, these clinical entities are considered as PPi deficiency disorders, serving as paradigms of ectopic calcification 7 . Despite significant progress in understanding the pathomechanisms from ABCC6 deficiency to ectopic calcification, PXE remains as an intractable disease.…”

Section: Introductionmentioning

confidence: 99%

INZ‐701, a recombinant ENPP1 enzyme, prevents ectopic calcification in an Abcc6^−/− mouse model of pseudoxanthoma elasticum

Jacobs

Cheng²,

Ralph

et al. 2022

Experimental Dermatology

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Pseudoxanthoma elasticum (PXE), a heritable multisystem ectopic calcification disorder, is predominantly caused by inactivating mutations in ABCC6. The encoded protein, ABCC6, is a hepatic efflux transporter and a key regulator of extracellular inorganic pyrophosphate (PPi). Recent studies demonstrated that deficiency of plasma PPi, a potent endogenous calcification inhibitor, is the underlying cause of PXE. This study examined whether restoring plasma PPi levels by INZ-701, a recombinant human ENPP1 protein, the principal PPi-generating enzyme, prevents ectopic calcification in an Abcc6 −/− mouse model of PXE. Abcc6 −/− mice, at 6 weeks of age, the time of earliest stages of ectopic calcification, were injected subcutaneously with INZ-701 at 2 or 10 mg/kg for 2 or 8 weeks. INZ-701 at both doses increased steady-state plasma ENPP1 activity and PPi levels. In the 8-week treatment study, histopathologic examination and quantification of the calcium content in INZ-701-treated Abcc6 −/− mice revealed significantly reduced calcification in the muzzle skin containing vibrissae, a biomarker of the calcification process in these mice. The extent of calcification corresponds to the local expression of two calcification inhibitors, osteopontin and fetuin-A. These results suggest that INZ-701 might provide a therapeutic approach for PXE, a disease with high unmet needs and no approved treatment.

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“…For a long time, ectopic calcification was considered to be a passive process but recent discoveries proved that it is not the case, and identified numerous regulators of the calcification process. For example, studies on patients with rare inherited calcification syndromes such as pseudoxanthoma elasticum, generalized arterial calcification in infancy, and arterial calcification due to deficiency of CD73 led to the identification of inorganic pyrophosphate (PPi) as the principal physiologic inhibitor of hydroxyapatite deposition in soft tissues [ 8 , 9 , 10 , 11 ]. These hereditary disorders are caused by monogenic mutations in genes encoding key proteins in PPi metabolism such as ATP binding cassette subfamily C member 6, ectonucleotide pyrophosphatase/phosphodiesterase 1, and CD73 proteins, leading to reduced circulating levels of PPi [ 8 , 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Activation of Nrf2/HO-1 Antioxidant Pathway by Heme Attenuates Calcification of Human Lens Epithelial Cells

et al. 2022

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Cataract, an opacification in the crystalline lens, is a leading cause of blindness. Deposition of hydroxyapatite occurs in a cataractous lens that could be the consequence of osteogenic differentiation of lens epithelial cells (LECs). Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the transcription of a wide range of cytoprotective genes. Nrf2 upregulation attenuates cataract formation. Here we aimed to investigate the effect of Nrf2 system upregulation in LECs calcification. We induced osteogenic differentiation of human LECs (HuLECs) with increased phosphate and calcium-containing osteogenic medium (OM). OM-induced calcium and osteocalcin deposition in HuLECs. We used heme to activate Nrf2, which strongly upregulated the expression of Nrf2 and heme oxygenase-1 (HO-1). Heme-mediated Nrf2 activation was dependent on the production of reactive oxygens species. Heme inhibited Ca deposition, and the OM-induced increase of osteogenic markers, RUNX2, alkaline phosphatase, and OCN. Anti-calcification effect of heme was lost when the transcriptional activity of Nrf2 or the enzyme activity of HO-1 was blocked with pharmacological inhibitors. Among products of HO-1 catalyzed heme degradation iron mimicked the anti-calcification effect of heme. We concluded that heme-induced upregulation of the Nrf2/HO-1 system inhibits HuLECs calcification through the liberation of heme iron.

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Inorganic Pyrophosphate Deficiency Syndromes and Potential Treatments for Pathologic Tissue Calcification

Cited by 33 publications

References 51 publications

ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification

ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification

INZ‐701, a recombinant ENPP1 enzyme, prevents ectopic calcification in an Abcc6^−/− mouse model of pseudoxanthoma elasticum

Activation of Nrf2/HO-1 Antioxidant Pathway by Heme Attenuates Calcification of Human Lens Epithelial Cells

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Inorganic Pyrophosphate Deficiency Syndromes and Potential Treatments for Pathologic Tissue Calcification

Cited by 33 publications

References 51 publications

ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification

ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification

INZ‐701, a recombinant ENPP1 enzyme, prevents ectopic calcification in an Abcc6−/− mouse model of pseudoxanthoma elasticum

Activation of Nrf2/HO-1 Antioxidant Pathway by Heme Attenuates Calcification of Human Lens Epithelial Cells

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INZ‐701, a recombinant ENPP1 enzyme, prevents ectopic calcification in an Abcc6^−/− mouse model of pseudoxanthoma elasticum