The mineralization process of insoluble elastin fibrillar structures: Ionic environment vs degradation

Boraldi, Federica; Moscarelli, Pasquale; Lofaro, Francesco Demetrio; Sabia, Carla; Quaglino, Daniela

doi:10.1016/j.ijbiomac.2020.01.250

Cited by 22 publications

(20 citation statements)

References 62 publications

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“…The factor/s triggering the initial core of hydroxyapatite deposition still has/have to be identified. Degraded elastin fragments, per se, can expose multiple charged sites, favoring interactions with calcium and phosphate (Boraldi et al, 2020b). In addition, pro-osteogenic stimuli driven by necrotic cell debris, inflammatory cytokines, or unbalanced calciumphosphate homeostasis can modify the transcriptional program and promote the differentiation of soft connective tissue mesenchymal cells into osteogenic cells releasing bone-related molecules (Mathieu and Boulanger, 2014).…”

Section: Introductionmentioning

confidence: 99%

Relationship Between Mitochondrial Structure and Bioenergetics in Pseudoxanthoma elasticum Dermal Fibroblasts

Lofaro

Boraldi

García-Fernández

et al. 2020

Front. Cell Dev. Biol.

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Pseudoxanthoma elasticum (PXE) is a genetic disease considered as a paradigm of ectopic mineralization disorders, being characterized by multisystem clinical manifestations due to progressive calcification of skin, eyes, and the cardiovascular system, resembling an age-related phenotype. Although fibroblasts do not express the pathogenic ABCC6 gene, nevertheless these cells are still under investigation because they regulate connective tissue homeostasis, generating the “arena” where cells and extracellular matrix components can promote pathologic calcification and where activation of pro-osteogenic factors can be associated to pathways involving mitochondrial metabolism. The aim of the present study was to integrate structural and bioenergenetic features to deeply investigate mitochondria from control and from PXE fibroblasts cultured in standard conditions and to explore the role of mitochondria in the development of the PXE fibroblasts’ pathologic phenotype. Proteomic, biochemical, and morphological data provide new evidence that in basal culture conditions (1) the protein profile of PXE mitochondria reveals a number of differentially expressed proteins, suggesting changes in redox balance, oxidative phosphorylation, and calcium homeostasis in addition to modified structure and organization, (2) measure of oxygen consumption indicates that the PXE mitochondria have a low ability to cope with a sudden increased need for ATP via oxidative phosphorylation, (3) mitochondrial membranes are highly polarized in PXE fibroblasts, and this condition contributes to increased reactive oxygen species levels, (4) ultrastructural alterations in PXE mitochondria are associated with functional changes, and (5) PXE fibroblasts exhibit a more abundant, branched, and interconnected mitochondrial network compared to control cells, indicating that fusion prevail over fission events. In summary, the present study demonstrates that mitochondria are modified in PXE fibroblasts. Since mitochondria are key players in the development of the aging process, fibroblasts cultured from aged individuals or aged in vitro are more prone to calcify, and in PXE, calcified tissues remind features of premature aging syndromes; it can be hypothesized that mitochondria represent a common link contributing to the development of ectopic calcification in aging and in diseases. Therefore, ameliorating mitochondrial functions and cell metabolism could open new strategies to positively regulate a number of signaling pathways associated to pathologic calcification.

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Section: Introductionmentioning

confidence: 99%

Relationship Between Mitochondrial Structure and Bioenergetics in Pseudoxanthoma elasticum Dermal Fibroblasts

Lofaro

Boraldi

García-Fernández

et al. 2020

Front. Cell Dev. Biol.

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“…preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted November 9, 2020. ; https://doi.org/10.1101/2020.11.07.20227512 doi: medRxiv preprint and proteases damage pulmonary elastic fibers [2]. These partially degraded fibers become more sensitive to calcium-ion binding [27], which in turn causes further degradation [29].…”

Section: Discussionmentioning

confidence: 99%

“…Elastic fibers have high affinity for calcium [25]. Calcification is a pathological process that stimulates elastic fiber degradation and vice versa [26, 27]. This may explain an accelerating effect of vitamin D on the rate of elastic fiber degradation.…”

Section: Discussionmentioning

confidence: 99%

“…During COVID-19, inflammatory infiltrates and proteases damage pulmonary elastic fibers [2]. These partially degraded fibers become more sensitive to calcium-ion binding [27], which in turn causes further degradation [29]. Through these mechanisms, vitamin D could both reduce inflammation by dampening cytokine response but increase proteolysis through calcification.…”

Section: Discussionmentioning

confidence: 99%

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Vitamin D – contrary to vitamin K – does not associate with clinical outcome in hospitalized COVID-19 patients

Walk

et al. 2020

Preprint

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SARS-CoV-2 causes remarkably variable disease from asymptomatic individuals to respiratory insufficiency and coagulopathy. Vitamin K deficiency was recently found to associate with clinical outcome in a cohort of COVID-19 patients. Vitamin D has been hypothesized to reduce disease susceptibility by modulating inflammation, yet little is known about its role in disease severity. Considering the critical interaction between vitamin K and vitamin D in calcium and elastic fiber metabolism, we determined vitamin D status in the same cohort of 135 hospitalized COVID-19 patients by measuring blood 25(OH)D levels. We found no difference in vitamin D status between those with good and poor outcome (defined as intubation and/or death). Instead, we found vitamin D sufficient persons (25(OH)D >50 nmol/L) had accelerated elastic fiber degradation compared to those with mild deficiency (25(OH)D 25-50 nmol/L). Based on these findings, we hypothesize that vitamin D might have both favorable anti-inflammatory and unfavorable pro-calcification effects during COVID-19 and that vitamin K might compensate for the latter.

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“…Their integrity and function may be hampered by proteolytic degradation as well as calcification. Partially degraded elastic fibers are particularly vulnerable to calcium because of their increased polarity [12]. Elastic fiber mineralization, on the other hand, may stimulate elastolysis as synthesis of proteases is upregulated in parallel to increasing calcium content [13].…”

Section: Endothelialitismentioning

confidence: 99%

Why Appreciation of Pulmonary Vitamin D Metabolism Should Temper Expectations for Vitamin D Supplementation to Reduce Disease Severity and Improve Clinical Outcome of COVID-19

Janssen¹,

Walk²,

Ouweland³

2020

Preprint

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Vitamin D is a nutrient with anti-inflammatory properties whose role is currently being evaluated in COVID-19. Although studies are conflicting, they seem to suggest a role for vitamin D in reducing disease susceptibility but not in improving clinical outcome. In order to understand why vitamin D does not seem to have much effect on decreasing disease severity, it is essential to appreciate pulmonary vitamin D metabolism. To reach the pulmonary compartment, vascular endothelial cells would need to take up vitamin D from the blood stream, but they lack vitamin D receptor (VDR) and the activating enzyme CYP27B1. Endothelialitis – an important disease manifestation of COVID-19 – is therefore not expected to be directly affected by vitamin D. Bronchial epithelial cells are usually among the first to be infected with SARS-CoV-2. They do express both VDR and CYP27B1, but circulating vitamin D may not reach bronchial epithelial cells without transportation from the blood stream through the blood vessel wall. Inhalation therapy with vitamin D has therefore been suggested as an alternative for oral administration to bypass endothelial cells and efficaciously target bronchial epithelium. In conclusion, based on the principles of pulmonary vitamin D metabolism, it is not expected that vitamin D administration has a significant effect on COVID-19 severity. Vitamin D is more likely to reduce SARS-CoV-2 susceptibility, but reaching the airways with oral supplementation will be difficult and vitamin D inhalation therapy should be considered.

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The mineralization process of insoluble elastin fibrillar structures: Ionic environment vs degradation

Cited by 22 publications

References 62 publications

Relationship Between Mitochondrial Structure and Bioenergetics in Pseudoxanthoma elasticum Dermal Fibroblasts

Relationship Between Mitochondrial Structure and Bioenergetics in Pseudoxanthoma elasticum Dermal Fibroblasts

Vitamin D – contrary to vitamin K – does not associate with clinical outcome in hospitalized COVID-19 patients

Why Appreciation of Pulmonary Vitamin D Metabolism Should Temper Expectations for Vitamin D Supplementation to Reduce Disease Severity and Improve Clinical Outcome of COVID-19

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