Warfarin Accelerates Ectopic Mineralization in Abcc6−/− Mice

Li, Qiaoli; Guo, Haitao; Chou, David; Harrington, Dominic J.; Schurgers, Leon J.; Terry, Sharon F.; Uitto, Jouni

doi:10.1016/j.ajpath.2012.12.037

Cited by 21 publications

(16 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Arterial calcification has been reported in patients using vitamin K antagonists such as warfarin, probably due to undercarboxylation of OC, GRP and especially MGP (Chatrou et al, 2012;Theuwissen et al, 2012). 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: 79%

See 1 more Smart Citation

Vitamin K reduces hypermineralisation in zebrafish models of PXE and GACI

2015

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionsupporting

confidence: 79%

“…As warfarin has been reported to accelerate the mineralisation phenotype of Abcc6 −/− mice (Li et al, 2013), we raised grt −/− zebrafish embryos in the presence of sodium warfarin from 4-8 dpf. Mortality was observed at concentrations exceeding 120 µM.…”

Section: Vitamin K Reduces Hypermineralisationmentioning

confidence: 99%

Vitamin K reduces hypermineralisation in zebrafish models of PXE and GACI

2015

View full text Add to dashboard Cite

show abstract

“…While the mineral deposits in soft tissues of Abcc6 −/− mice have been shown to consist of calcium hydroxyapatite [21, 22], the pathomechanistic pathways resulting in aberrant mineral deposits are currently unknown. Thus, it is not clear how statins might elicit reduction of mineral deposition in these mice and whether the effect is related to the inhibition of the cholesterol pathway.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin counteracts aberrant soft tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6 −/− )

Guo

Chou

et al. 2013

J Mol Med

Self Cite

View full text Add to dashboard Cite

Pseudoxanthoma elasticum (PXE), a multisystem heritable disorder with aberrant mineralization of arterial blood vessels, is caused by mutations in the ABCC6 gene. Previous studies have suggested that carriers of the ABCC6 mutations, particularly of p.R1141X, are at increased risk for coronary artery disease. In this study, we used Abcc6tm1Jfk knock-out mice to determine the serum lipid profiles and examine the effects of atorvastatin on the aberrant mineralization in this model of PXE. First, serum lipid profiles at 12 weeks of age, after overnight fasting, revealed a statistically significant increase in total cholesterol and triglyceride levels in Abcc6tm1Jfk mice compared to their wild-type littermates. Placing these mice at 4 weeks of age for 20 weeks on atorvastatin, either 0.01% or 0.04% of the diet (low statin and high statin groups, respectively), reduced the total triglyceride and cholesterol levels, which was accompanied with significantly reduced mineralization of the dermal sheath of vibrissae, a biomarker of the aberrant mineralization process in these mice. However, if the mice were placed on atorvastatin for 12 weeks at 12 weeks of age, at which time point significant mineralization had already taken place, no difference in the amount of mineralization was noted. These observations suggest that statins, particularly atorvastatin, can prevent, but not reverse, aberrant mineralization in this mouse model of PXE. For a clinical perspective, a survey of 1,747 patients with PXE was conducted regarding their present or past use of statins. The results indicated that about one third of all PXE patients are currently or have previously been on cholesterol-lowering drugs. Thus, a sizable number of patients with PXE could be subject to modulation of their mineralization processes by concomitant statin treatment.

show abstract

“…None of these treatments counteracted the mineralization of connective tissues in this mouse model of PXE (Brampton et al, 2011; Gorgels et al, 2011; Jiang et al, 2011). It has been demonstrated, however, that feeding Abcc6 ‒/‒ mice with warfarin, an anticoagulant that interferes with the vitamin K cycle by preventing the reduction of the oxidized form of vitamin K (epoxide) to its reduced form (hydroquinone), dramatically increased the accumulation of mineral deposits in soft connective tissues in comparison to Abcc6 ‒/‒ mice kept on control diet (Li et al, 2013c). While these results do not unequivocally establish a role for vitamin K deficiency in the development of mineral deposits in PXE, they suggest that reduction in the γ-glutamyl carboxylation of MGP by warfarin can result severe ectopic mineralization, with apparent clinical implication that patients with PXE on warfarin therapy may be at risk of worsening their disease.…”

Section: Heritable Disorders With Connective Tissue Mineralizationmentioning

confidence: 99%

Ectopic mineralization disorders of the extracellular matrix of connective tissue: Molecular genetics and pathomechanisms of aberrant calcification

Jiang

Uitto

2014

Matrix Biology

Self Cite

View full text Add to dashboard Cite

Ectopic mineralization of connective tissues is a complex process leading to deposition of calcium phosphate complexes in the extracellular matrix, particularly affecting the skin and the arterial blood vessels and common in age-associated disorders. A number of initiating and contributing metabolic and environmental factors are linked to aberrant mineralization in these diseases, making the identification of precise pathomechanistic pathways exceedingly difficult. However, there has been significant recent progress in understanding the ectopic mineralization processes through study of heritable single-gene disorders, which have allowed identification of discreet pathways and contributing factors leading to aberrant connective tissue mineralization. These studies have provided support for the concept of an intricate mineralization/anti-mineralization network present in peripheral connective tissues, providing a perspective to development of pharmacologic approaches to limit the phenotypic consequences of ectopic mineralization. This overview summarizes the current knowledge of ectopic heritable mineralization disorders, with accompanying animal models, focusing on pseudoxanthoma elasticum and generalized arterial calcification of infancy, two autosomal recessive diseases manifesting with extensive connective tissue mineralization in the skin and the cardiovascular system.

show abstract

Warfarin Accelerates Ectopic Mineralization in Abcc6−/− Mice

Cited by 21 publications

References 48 publications

Vitamin K reduces hypermineralisation in zebrafish models of PXE and GACI

Vitamin K reduces hypermineralisation in zebrafish models of PXE and GACI

Atorvastatin counteracts aberrant soft tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6 −/− )

Ectopic mineralization disorders of the extracellular matrix of connective tissue: Molecular genetics and pathomechanisms of aberrant calcification

Contact Info

Product

Resources

About