Administration of vitamin K does not counteract the ectopic mineralization of connective tissues in<i>Abcc6</i><sup>-/-</sup>mice, a model for pseudoxanthoma elasticum

Jiang, Qiujie; Li, Qiaoli; Grand-Pierre, Alix E.; Schurgers, Leon J.; Uitto, Jouni

doi:10.4161/cc.10.4.14862

Cited by 45 publications

(42 citation statements)

References 30 publications

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“…Similar results were obtained in Abcc6 −/− mice (Li et al, 2013). However, ectopic mineralisation in Abcc6 −/− mice was not reduced by dietary administration of vitamin K 1 or K 2 (Brampton et al, 2011;Gorgels et al, 2011;Jiang et al, 2011) despite successfully raising the vitamin K concentration in tissues and serum; interestingly, this increase was significantly subdued in knockout mice and was accompanied by hepatic lesions, suggesting that Abcc6 −/− mice have an impaired ability to absorb, metabolise or distribute vitamin K (Brampton et al, 2011).…”

Section: Introductionsupporting

confidence: 72%

Vitamin K reduces hypermineralisation in zebrafish models of PXE and GACI

2015

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The mineralisation disorder pseudoxanthoma elasticum (PXE) is associated with mutations in the transporter protein ABCC6. Patients with PXE suffer from calcified lesions in the skin, eyes and vasculature, and PXE is related to a more severe vascular calcification syndrome called generalised arterial calcification of infancy (GACI). Mutations in ABCC6 are linked to reduced levels of circulating vitamin K. Here, we describe a mutation in the zebrafish (Danio rerio) orthologue abcc6a, which results in extensive hypermineralisation of the axial skeleton. Administration of vitamin K to embryos was sufficient to restore normal levels of mineralisation. Vitamin K also reduced ectopic mineralisation in a zebrafish model of GACI, and warfarin exacerbated the mineralisation phenotype in both mutant lines. These data suggest that vitamin K could be a beneficial treatment for human patients with PXE or GACI. Additionally, we found that abcc6a is strongly expressed at the site of mineralisation rather than the liver, as it is in mammals, which has significant implications for our understanding of the function of ABCC6.

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Section: Introductionsupporting

confidence: 72%

Vitamin K reduces hypermineralisation in zebrafish models of PXE and GACI

2015

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“…In addition, the demonstration that vit K supplementation does not counteract soft connective tissue mineralization in the PXE animal model (Brampton et al, 2011;Gorgels et al, 2011;Jiang et al, 2011) poses the question whether PXE fibroblasts are unable to utilize the vitamin (Boraldi et al, 2009).…”

Section: Vit K Uptake By Dermal Fibroblasts and Cell Viabilitymentioning

confidence: 98%

“…In this scenario, it has been suggested that vit K supplementation might be capable of restoring MGP carboxylation and to inhibit ectopic calcifications (Borst et al, 2008). However, recent studies in the PXE animal model (ABCC6 À / À mice) demonstrated that vit K supplementation does not counteract the mineralization of soft connective tissues (Brampton et al, 2011;Gorgels et al, 2011;Jiang et al, 2011). Key question is whether PXE fibroblasts are able to utilize vit K and restore an adequate MGP carboxylation.…”

Section: Introductionmentioning

confidence: 94%

Matrix Gla Protein and Alkaline Phosphatase Are Differently Modulated in Human Dermal Fibroblasts from PXE Patients and Controls

Boraldi

Annovi

Vermeer

et al. 2013

Journal of Investigative Dermatology

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Mineralization of elastic fibers in pseudoxanthoma elasticum (PXE) has been associated with low levels of carboxylated matrix gla protein (MGP), most likely as a consequence of reduced vitamin K (vit K) availability. Unexpectedly, vit K supplementation does not exert beneficial effects on soft connective tissue mineralization in the PXE animal model. To understand the effects of vit K supplementation and in the attempt to interfere with pathways leading to the accumulation of calcium and phosphate within PXE-mineralized soft connective tissues, we have conducted in vitro studies on dermal fibroblasts isolated from control subjects and from PXE patients. Cells were cultured in standard conditions and in calcifying medium (CM) in the presence of vit K1 and K2, or levamisole, an alkaline phosphatase (ALP) inhibitor. Control and PXE fibroblasts were characterized by a similar dose-dependent uptake of both vit K1 and vit K2, thus promoting a significant increase of total protein carboxylation in all cell lines. Nevertheless, MGP carboxylation remained much less in PXE fibroblasts. Interestingly, PXE fibroblasts exhibited a significantly higher ALP activity. Consistently, the mineralization process induced in vitro by a long-term culture in CM appeared unaffected by vit K, whereas it was abolished by levamisole.

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“…In three separate animal studies, oral administration of high doses of vitamin K yielded elevated vitamin serum levels, but this elevation was insufficient to counteract ectopic mineralization in kidney arteries [51] and connective tissue surrounding the vibrissae of the Abcc6-deficient mouse [51][52][53]. These observations were affirmed by intravenous vitamin K administration in which vitamin K supply to peripheral tissue via the liver was bypassed, thus assuring that potentially defective hepatic Abcc6 protein did not affect vitamin K levels in peripheral tissues of Abcc6 −/− mice [52]. Altogether, the available data suggest that oral vitamin K supplements cannot ameliorate the calcification phenotype of Abcc6 −/− mice.…”

Section: Investigations Of Vitamin K and Adenosine As Candidate Abcc6 Smentioning

confidence: 99%

Is classical pseudoxanthoma elasticum a consequence of hepatic ‘intoxication’ due to ABCC6 substrate accumulation in the liver?

Rasmussen¹,

Sommerlund²,

Moestrup³

2013

Expert Review of Endocrinology & Metabolism

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Administration of vitamin K does not counteract the ectopic mineralization of connective tissues inAbcc6^-/-mice, a model for pseudoxanthoma elasticum

Cited by 45 publications

References 30 publications

Vitamin K reduces hypermineralisation in zebrafish models of PXE and GACI

Vitamin K reduces hypermineralisation in zebrafish models of PXE and GACI

Matrix Gla Protein and Alkaline Phosphatase Are Differently Modulated in Human Dermal Fibroblasts from PXE Patients and Controls

Is classical pseudoxanthoma elasticum a consequence of hepatic ‘intoxication’ due to ABCC6 substrate accumulation in the liver?

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Administration of vitamin K does not counteract the ectopic mineralization of connective tissues inAbcc6-/-mice, a model for pseudoxanthoma elasticum

Cited by 45 publications

References 30 publications

Vitamin K reduces hypermineralisation in zebrafish models of PXE and GACI

Vitamin K reduces hypermineralisation in zebrafish models of PXE and GACI

Matrix Gla Protein and Alkaline Phosphatase Are Differently Modulated in Human Dermal Fibroblasts from PXE Patients and Controls

Is classical pseudoxanthoma elasticum a consequence of hepatic ‘intoxication’ due to ABCC6 substrate accumulation in the liver?

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Administration of vitamin K does not counteract the ectopic mineralization of connective tissues inAbcc6^-/-mice, a model for pseudoxanthoma elasticum