Pseudoxanthoma elasticum: Reduced γ-glutamyl carboxylation of matrix gla protein in a mouse model (Abcc6−−)

Li, Qiaoli; Jiang, Qiujie; Schurgers, Leon J.; Uitto, Jouni

doi:10.1016/j.bbrc.2007.09.122

Cited by 62 publications

(54 citation statements)

References 22 publications

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“…The reduced serum fetuin A levels in Abcc6 −/− mice might be related to binding of circulating fetuin A to the mineralizing lesions, as observed in other mineralization disorders (43). Similarly, matrix Gla protein (MGP) was found to be reduced and undercarboxylated in PXE patients and Abcc6 −/− mice (44,45). Given that carboxylated MGP binds to hydroxyapatite crystals, the reduced MGP levels could be secondary to mineralization rather than causative (46).…”

mentioning

confidence: 88%

ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release

Jansen

Küçükosmanoğlu

Haas

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

235

310

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Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by progressive ectopic mineralization of the skin, eyes, and arteries, for which no effective treatment exists. PXE is caused by inactivating mutations in the gene encoding ATPbinding cassette sub-family C member 6 (ABCC6), an ATP-dependent efflux transporter present mainly in the liver. Abcc6 −/− mice have been instrumental in demonstrating that PXE is a metabolic disease caused by the absence of an unknown factor in the circulation, the presence of which depends on ABCC6 in the liver. Why absence of this factor results in PXE has remained a mystery. Here we report that medium from HEK293 cells overexpressing either human or rat ABCC6 potently inhibits mineralization in vitro, whereas medium from HEK293 control cells does not. Untargeted metabolomics revealed that cells expressing ABCC6 excrete large amounts of nucleoside triphosphates, even though ABCC6 itself does not transport nucleoside triphosphates. Extracellularly, ectonucleotidases hydrolyze the excreted nucleoside triphosphates to nucleoside monophosphates and inorganic pyrophosphate (PPi), a strong inhibitor of mineralization that plays a pivotal role in several mineralization disorders similar to PXE. The in vivo relevance of our data are demonstrated in Abcc6 −/− mice, which had plasma PPi levels <40% of those found in WT mice. This study provides insight into how ABCC6 affects PXE. Our data indicate that the factor that normally prevents PXE is PPi, which is provided to the circulation in the form of nucleoside triphosphates via an asyet unidentified but ABCC6-dependent mechanism.ATP secretion | ectopic calcification | MRP6 | ENPP1

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mentioning

confidence: 88%

ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release

Jansen

Küçükosmanoğlu

Haas

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

235

310

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“…In contrast, the small amounts of carboxylated MGP localized at the mineralization front. In the Abcc6 -/-mouse model Uitto and co-workers 28,29 found early calcification in the connective tissue capsule of the blood sinus surrounding the hair follicles in vibrissae. Normal capsules were devoid of MGP, but the mineralized capsules contained MGP and this was exclusively ucMGP, unable to counteract local tissue calcification.…”

Section: Pxe and Vitamin Kmentioning

confidence: 99%

Does the absence of ABCC6 (Multidrug Resistance Protein 6) in patients withPseudoxanthoma elasticumprevent the liver from providing sufficient vitamin K to the periphery?

Borst

Wetering²,

Schlingemann³

2008

Cell Cycle

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“…Recently reported findings already point toward a role of MGP in classic PXE, but neither the involvement of other Gla proteins nor the mechanism for such involvement have been studied yet. [19][20][21][22] Because of the remarkable phenotypical similarities of the PXE-like syndrome and PXE and the absence in PXE of GGCX or VKORC1 mutations, which both have the potential of disrupting the VK cycle, we wondered whether the VK cycle could also be disturbed by another mechanism in PXE. More precisely, we hypothesized that disturbances in Gla proteins in PXE patients could be linked to VK, the co-factor in the VK cycle and an essential mediator of Gla-protein carboxylation.…”

mentioning

confidence: 99%

Low serum vitamin K in PXE results in defective carboxylation of mineralization inhibitors similar to the GGCX mutations in the PXE-like syndrome

Vanakker

Martin

Schurgers

et al. 2010

Laboratory Investigation

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Soft-tissue mineralization is a tightly regulated process relying on the activity of systemic and tissue-specific inhibitors and promoters of calcium precipitation. Many of these, such as matrix gla protein (MGP) and osteocalcin (OC), need to undergo carboxylation to become active. This post-translational modification is catalyzed by the gammaglutamyl carboxylase GGCX and requires vitamin K (VK) as an essential co-factor. Recently, we described a novel phenotype characterized by aberrant mineralization of the elastic fibers resulting from mutations in GGCX. Because of the resemblance with pseudoxanthoma elasticum (PXE), a prototype disorder of elastic fiber mineralization, it was coined the PXE-like syndrome. As mutations in GGCX negatively affect protein carboxylation, it is likely that inactive inhibitors of calcification contribute to ectopic mineralization in PXE-like syndrome. Because of the remarkable similarities with PXE, we performed a comparative study of various forms of VK-dependent proteins in serum, plasma (using ELISA), and dermal tissues (using immunohistochemistry) of PXE-like and PXE patients using innovative, conformation-specific antibodies. Furthermore, we measured VK serum concentrations (using HPLC) in PXE-like and PXE samples to evaluate the VK status. In PXE-like patients, we noted an accumulation of uncarboxylated Gla proteins, MGP, and OC in plasma, serum, and in the dermis. Serum levels of VK were normal in these patients. In PXE patients, we found similar, although not identical results for the Gla proteins in the circulation and dermal tissue. However, the VK serum concentration in PXE patients was significantly decreased compared with controls. Our findings allow us to conclude that ectopic mineralization in the PXE-like syndrome and in PXE results from a deficient protein carboxylation of VK-dependent inhibitors of calcification. Although in PXE-like patients this is due to mutations in the GGCX gene, a deficiency of the carboxylation co-factor VK is at the basis of the decreased activity of calcification inhibitors in PXE.

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Pseudoxanthoma elasticum: Reduced γ-glutamyl carboxylation of matrix gla protein in a mouse model (Abcc6−−)

Cited by 62 publications

References 22 publications

ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release

ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release

Does the absence of ABCC6 (Multidrug Resistance Protein 6) in patients withPseudoxanthoma elasticumprevent the liver from providing sufficient vitamin K to the periphery?

Low serum vitamin K in PXE results in defective carboxylation of mineralization inhibitors similar to the GGCX mutations in the PXE-like syndrome

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