Parabiotic Heterogenetic Pairing of Abcc6−/−/Rag1−/− Mice and Their Wild-Type Counterparts Halts Ectopic Mineralization in a Murine Model of Pseudoxanthoma Elasticum

Jiang, Qiujie; Oldenburg, Reid; Otsuru, Satoru; Grand-Pierre, Alix E.; Horwitz, Edwin M.; Uitto, Jouni

doi:10.2353/ajpath.2010.090983

Cited by 62 publications

(57 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Transplanting skin from wild-type mice onto Abcc6 −/− animals resulted in mineralisation of the grafted tissue, whereas the reverse operation did not (Jiang et al, 2008). Surgical joining ( parabiosis) of Abcc6 −/− and wild-type mice halted ectopic mineralisation in the knockout animal (Jiang et al, 2010b), suggesting that the blood of wild-type mice carries an as-yet-unknown anti-mineralisation factor. One candidate for this factor is fetuin-A (alpha-2-HS-glycoprotein/Ahsg), a small liverderived protein which can inhibit hydroxyapatite precipitation (Schäfer et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

Vitamin K reduces hypermineralisation in zebrafish models of PXE and GACI

2015

View full text Add to dashboard Cite

show abstract

“…PXE is a metabolic disease caused by the absence of a factor, the presence of which depends on ABCC6 in the liver (17). Jiang and coworkers (14,18) previously showed that in an in vitro system using vascular smooth muscle cells, serum from Abcc6 +/+ mice inhibits mineralization to a greater extent than serum from Abcc6 −/− mice. We took a similar approach to test whether a mineralization-inhibiting factor is also present in medium from HEK293 cells overexpressing human ABCC6 (HEK293/hABCC6) or rat ABCC6 (HEK293/rABCC6).…”

Section: Abcc6-conditioned Medium Inhibits Mineralization Inmentioning

confidence: 99%

“…Abcc6 −/− muzzle skin that mineralizes in Abcc6 −/− mice does not mineralize when grafted onto WT mice, and muzzle skin of WT mice mineralizes only when grafted onto Abcc6 −/− mice (17). Moreover, surgically joining the systemic circulation of Abcc6 −/− mice with that of WT mice halts mineralization in Abcc6 −/− mice (18). Thus, PXE is caused not by a lack of functional ABCC6 in the affected tissues, but rather by the absence of a factor that is normally provided to the circulation by an ABCC6-dependent mechanism.…”

mentioning

confidence: 99%

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

View full text Add to dashboard Cite

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

show abstract

“…Parabiotic surgery was performed as described previously [40][41][42]. A male Nes-Cre; R26-EYFP or Nes-Cre (control) mouse was surgically joined to a male ldlr -/ -mouse.…”

Section: Parabiosismentioning

confidence: 99%

Mesenchymal Stem Cells Recruited by Active TGFβ Contribute to Osteogenic Vascular Calcification

Wang

Pang

et al. 2014

Stem Cells and Development

View full text Add to dashboard Cite

Vascular calcification is an actively regulated process that culminates in organized extracellular matrix mineral deposition by osteoblast-like cells. The origins of the osteoblastic cells involved in this process and the underlying mechanisms remain to be defined. We previously revealed that active transforming growth factor (TGFb) released from the injured arteries mobilizes mesenchymal stem cells (MSCs) to the blood stream and recruits the cells to the injured vessels for neointima formation. In this study, we used a low-density lipoprotein receptor (LDLR)-deficient mouse model (ldlr -/ -), which develop progressive arterial calcification after having fed high-fat western diets (HFD), to examine whether TGFb is involved in the mobilization of MSCs during vascular calcification. Nestin + /Sca1 + cells were recruited to the diseased aorta at earlier time points, and osteocalcin + osteoblasts and the aortic calcification were seen at later time point in these mice. Importantly, we generated parabiotic pairs with shared blood circulation by crossing ldlr -/ -mice fed HFD with transgenic mice, in which all the MSC-derived cells were fluorescently labeled. The labeled cells were detected not only in the peripheral blood but also in the arterial lesions in ldlr -/ -mouse partners, and these blood circulation-originated cells gave rise to Ocn + osteoblastic cells at the arterial lesions. Both active TGFb1 levels and MSCs in circulating blood were upregulated at the same time points when these cells appeared at the aortic tissue. Further, conditioned medium prepared by incubating the aortae from ldlr -/ -mice fed HFD stimulated the migration of MSCs in the ex vivo transwell assays, and either TGFb neutralizing antibody or the inhibitor of TGFb Receptor I kinase (TbRI) antagonized this effect. Importantly, treatment of the mice with TbRI inhibitor blocked elevated blood MSC numbers and their recruitment to the arterial lesions. These findings suggest that TGFb-recruited MSCs to the diseased vasculature contribute to the development of osteogenic vascular calcification.

show abstract

Parabiotic Heterogenetic Pairing of Abcc6−/−/Rag1−/− Mice and Their Wild-Type Counterparts Halts Ectopic Mineralization in a Murine Model of Pseudoxanthoma Elasticum

Cited by 62 publications

References 28 publications

Vitamin K reduces hypermineralisation in zebrafish models of PXE and GACI

Vitamin K reduces hypermineralisation in zebrafish models of PXE and GACI

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

Mesenchymal Stem Cells Recruited by Active TGFβ Contribute to Osteogenic Vascular Calcification

Contact Info

Product

Resources

About