Vitamin K reduces hypermineralisation in zebrafish models of PXE and GACI

Mackay, Eirinn; Apschner, Alexander; Schulte‐Merker, Stefan

doi:10.1242/dev.113811

Cited by 44 publications

(70 citation statements)

References 45 publications

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“…Such analysis provided further insights into the mineralogenic effects related to bone density or ray thickness and is, therefore, a complement to other techniques that infer on the organization of the regenerated mineral, such as birefringence analysis1358, for the identification of pro- or anti-mineralogenic agents with effects not as evident as those of RA, for example. Our data confirmed the role of WARF in negatively regulating mineral density in zebrafish lepidotrichia, in a way contrasting to that described for the abcc6a mutant57. This can be simply explained by the fact that those are two distinct mineralizing systems.…”

Section: Resultssupporting

confidence: 82%

“…Interestingly, in vitro studies reported an inhibition of osteoblast differentiation upon WARF exposure54, while VK media supplementation promoted osteoblast-to-osteocyte transition and decreased osteoclast differentiation5556. Exposure of zebrafish to WARF was found to induce pathological calcification of soft tissues and altered skeletal development during larval stages27, and to promote axial skeleton mineralization in an abcc6a mutant, while VK inhibited bone matrix mineralization57.…”

Section: Resultsmentioning

confidence: 99%

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Quantitative assessment of the regenerative and mineralogenic performances of the zebrafish caudal fin

Cardeira

Gavaia

Fernández

et al. 2016

Sci Rep

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The ability of zebrafish to fully regenerate its caudal fin has been explored to better understand the mechanisms underlying de novo bone formation and to develop screening methods towards the discovery of compounds with therapeutic potential. Quantifying caudal fin regeneration largely depends on successfully measuring new tissue formation through methods that require optimization and standardization. Here, we present an improved methodology to characterize and analyse overall caudal fin and bone regeneration in adult zebrafish. First, regenerated and mineralized areas are evaluated through broad, rapid and specific chronological and morphometric analysis in alizarin red stained fins. Then, following a more refined strategy, the intensity of the staining within a 2D longitudinal plane is determined through pixel intensity analysis, as an indicator of density or thickness/volume. The applicability of this methodology on live specimens, to reduce animal experimentation and provide a tool for in vivo tracking of the regenerative process, was successfully demonstrated. Finally, the methodology was validated on retinoic acid- and warfarin-treated specimens, and further confirmed by micro-computed tomography. Because it is easily implementable, accurate and does not require sophisticated equipment, the present methodology will certainly provide valuable technical standardization for research in tissue engineering, regenerative medicine and skeletal biology.

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Section: Resultssupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Quantitative assessment of the regenerative and mineralogenic performances of the zebrafish caudal fin

Cardeira

Gavaia

Fernández

et al. 2016

Sci Rep

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“…1C-E), appearing like a subtle craniosynostosis. However, this ectopic mineralization does not seem to occur in intercalvarial regions, but primarily in the adjacent dermis, as described for diseases such as pseudoxanthoma elasticum (PXE) (Apschner et al, 2014;Mackay et al, 2015;Walker et al, 1989). Indeed, both dermal fibroblasts and basal keratinocytes express col1a2 (Fig.…”

Section: Discussionmentioning

confidence: 80%

Retinoic acid-induced premature osteoblast-to-preosteocyte transitioning has multiple effects on calvarial development

Jeradi

Hammerschmidt

2016

Development

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We have previously shown that, in human and zebrafish, hypomorphic mutations of the gene encoding the retinoic acid (RA)-metabolizing enzyme Cyp26b1 result in coronal craniosynostosis, caused by an RA-induced premature transitioning of suture osteoblasts to preosteocytes, inducing ectopic mineralization of the suture's osteoid matrix. In addition, we showed that human CYP26B1 null patients have more severe and seemingly opposite skull defects, characterized by smaller and fragmented calvaria, but the cellular basis of these defects remained largely unclear. Here, by treating juvenile zebrafish with exogenous RA or a chemical Cyp26 inhibitor in the presence or absence of osteogenic cells or bone-resorbing osteoclasts, we demonstrate that both reduced calvarial size and calvarial fragmentation are also caused by RA-induced premature osteoblast-to-preosteocyte transitioning. During calvarial growth, the resulting osteoblast deprival leads to decreased osteoid production and thereby smaller and thinner calvaria, whereas calvarial fragmentation is caused by increased osteoclast stimulation through the gained preosteocytes. Together, our data demonstrate that RAinduced osteoblast-to-preosteocyte transitioning has multiple effects on developing bone in Cyp26b1 mutants, ranging from gain to loss of bone, depending on the allelic strength, the developmental stage and the cellular context.

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“…On the basis of animal model experiments, it has also been hypothesized that low vitamin K export from the liver would decrease the gamma-carboxylation of anti-mineralization proteins [76, 77]. Furthermore, MGP is not carboxylated in the elastic fibers of PXE patients [78], and PXE-like calcification of elastic fibers is observed in patients with mutation in the GGCX gene [78].…”

Section: Etiologymentioning

confidence: 99%

“…Most of the detailed experimental data on the pathophysiology of PXE comes from Abcc6 -deficient models in the zebrafish [77, 96, 97] and in the mouse [98–102]. The zebrafish model is a useful tool for testing potential therapies, such as premature termination codon read-through [103].…”

Section: Etiologymentioning

confidence: 99%

Pseudoxanthoma elasticum

Germain

2017

Orphanet J Rare Dis

144

147

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Pseudoxanthoma elasticum (PXE) is a genetic metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. The lack of functional ABCC6 protein leads to ectopic mineralization that is most apparent in the elastic tissues of the skin, eyes and blood vessels. The clinical prevalence of PXE has been estimated at between 1 per 100,000 and 1 per 25,000, with slight female predominance. The first clinical sign of PXE is almost always small yellow papules on the nape and sides of the neck and in flexural areas. The papules coalesce, and the skin becomes loose and wrinkled. The mid-dermal elastic fibers are short, fragmented, clumped and calcified. Dystrophic calcification of Bruch’s membrane, revealed by angioid streaks, may trigger choroidal neovascularization and, ultimately, loss of central vision and blindness in late-stage disease. Lesions in small and medium-sized artery walls may result in intermittent claudication and peripheral artery disease. Cardiac complications (myocardial infarction, angina pectoris) are thought to be relatively rare but merit thorough investigation. Ischemic strokes have been reported. PXE is a metabolic disease in which circulating levels of an anti-mineralization factor are low. There is good evidence to suggest that the factor is inorganic pyrophosphate (PPi), and that the circulating low levels of PPi and decreased PPi/Pi ratio result from the lack of ATP release by hepatocytes harboring the mutant ABCC6 protein. However, the substrate(s) bound, transported or modulated by the ABCC6 protein remain unknown. More than 300 sequence variants of the ABCC6 gene have been identified. There is no cure for PXE; the main symptomatic treatments are vascular endothelial growth factor inhibitor therapy (for ophthalmic manifestations), lifestyle, lipid-lowering and dietary measures (for reducing vascular risk factors), and vascular surgery (for severe cardiovascular manifestations). Future treatment options may include gene therapy/editing and pharmacologic chaperone therapy.

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Vitamin K reduces hypermineralisation in zebrafish models of PXE and GACI

Cited by 44 publications

References 45 publications

Quantitative assessment of the regenerative and mineralogenic performances of the zebrafish caudal fin

Quantitative assessment of the regenerative and mineralogenic performances of the zebrafish caudal fin

Retinoic acid-induced premature osteoblast-to-preosteocyte transitioning has multiple effects on calvarial development

Pseudoxanthoma elasticum

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