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Ectopic Calcification in Hereditary and Acquired Diseases: From Bench to Bedside

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 18249

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Special Issue Editors

Dr. Tamas Aranyi

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Guest Editor

1. Institute of Enzymology, Research Center for Natural Sciences, Budapest, Hungary
2. Department of Molecular Biology, Semmelweis University, Budapest, Hungary
Interests: pseudoxanthoma elasticum; arterial calcification of infancy; epigenetics; DNA methylation; incomplete penetrance; conditional knock-out

Prof. Dr. Olivier M. Vanakker

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Guest Editor

Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
Interests: pseudoxanthoma elasticum; ectopic mineralization; mutations; mouse model; mutation; phenotype; PXE; calcification; abcc6 gene; intellectual disability; matrix Gla protein; mineralization

Dr. Flora Szeri

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Guest Editor

Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary
Interests: vascular biology; mineralization inhibitor; soft tissue calcification; arteriosclerosis; mineralization disorders; animal models; fetuin-A; alkaline phosphatase; pseudoxanthoma elasticum; arterial calcification; pyrophosphate; extracellular ATP; cardiovascular disease

Special Issue Information

Dear Colleagues,

Ectopic calcification (EC) is an inappropriate biomineralization occurring in soft tissues. Affecting a wide variety of tissues, EC is highly accelerated in aging and directly associated with morbidity and mortality in several rare hereditary conditions (e.g., pseudoxanthoma elasticum and GACI) and common diseases such as diabetes and chronic kidney disease (CKD). Though certain aspects of the pathophysiology between monogenic and acquired EC disorders vary, hereditary diseases provide a unique opportunity to identify the genetic background, pro- and anti-mineralization molecules and metabolic and epigenetic factors that contribute to the development, phenotypic consequences and severity of EC, which are translatable to common disorders and natural aging. However, despite its clinical and pathophysiological importance, the causes of EC are still obscure. This Special Issue will integrate the expertise of clinicians, basic scientists and patient organizations with two different points of view: rare monogenic EC and commonly acquired EC. By expanding the current knowledge of the underlying genetics, molecular mechanisms, risk factors and modulators behind similarities and differences in various forms of EC diseases, this Special Issue aims to contribute to improved risk stratification, prevention and diagnosis based on a deepened understanding of the causes and consequences of EC and will offer a unique collection stimulating future research and innovative therapeutic concepts.

Dr. Tamas Aranyi
Prof. Dr. Olivier M. Vanakker
Dr. Flóra Szeri
Guest Editors

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Published Papers (6 papers)

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Research

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22 pages, 4246 KiB

Open AccessArticle

Transcriptomic Differences Underlying the Activin-A Induced Large Osteoclast Formation in Both Healthy Control and Fibrodysplasia Ossificans Progressiva Osteoclasts

by Ton Schoenmaker, Joy Zwaak, Bruno G. Loos, Richard Volckmann, Jan Koster, E. Marelise W. Eekhoff and Teun J. de Vries

Int. J. Mol. Sci. 2023, 24(7), 6822; https://doi.org/10.3390/ijms24076822 - 6 Apr 2023

Cited by 3 | Viewed by 2187

Abstract

Fibrodysplasia Ossificans Progressiva (FOP) is a very rare genetic disease characterized by progressive heterotopic ossification (HO) of soft tissues, leading to immobility and premature death. FOP is caused by a mutation in the Activin receptor Type 1 (ACVR1) gene, resulting in altered responsiveness to Activin-A. We recently revealed that Activin-A induces fewer, but larger and more active, osteoclasts regardless of the presence of the mutated ACVR1 receptor. The underlying mechanism of Activin-A-induced changes in osteoclastogenesis at the gene expression level remains unknown. Transcriptomic changes induced by Activin-A during osteoclast formation from healthy controls and patient-derived CD14-positive monocytes were studied using RNA sequencing. CD14-positive monocytes from six FOP patients and six age- and sex-matched healthy controls were differentiated into osteoclasts in the absence or presence of Activin-A. RNA samples were isolated after 14 days of culturing and analyzed by RNA sequencing. Non-supervised principal component analysis (PCA) showed that samples from the same culture conditions (e.g., without or with Activin-A) tended to cluster, indicating that the variability induced by Activin-A treatment was larger than the variability between the control and FOP samples. RNA sequencing analysis revealed 1480 differentially expressed genes induced by Activin-A in healthy control and FOP osteoclasts with p(adj) < 0.01 and a Log2 fold change of ≥±2. Pathway and gene ontology enrichment analysis revealed several significantly enriched pathways for genes upregulated by Activin-A that could be linked to the differentiation or function of osteoclasts, cell fusion or inflammation. Our data showed that Activin-A has a substantial effect on gene expression during osteoclast formation and that this effect occurred regardless of the presence of the mutated ACVR1 receptor causing FOP. Full article

(This article belongs to the Special Issue Ectopic Calcification in Hereditary and Acquired Diseases: From Bench to Bedside)

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8 pages, 2356 KiB

Open AccessArticle

Fluorescence Lifetime Imaging of Human Sub-RPE Calcification In Vitro Following Chlortetracycline Infusion

by Kavita R. Hegde, Adam C. Puche, Henryk Szmacinski, Kristina Fuller, Krishanu Ray, Nikita Patel, Imre Lengyel and Richard B. Thompson

Int. J. Mol. Sci. 2023, 24(7), 6421; https://doi.org/10.3390/ijms24076421 - 29 Mar 2023

Cited by 3 | Viewed by 2051

Abstract

We have shown that all sub-retinal pigment epithelial (sub-RPE) deposits examined contain calcium phosphate minerals: hydroxyapatite (HAP), whitlockite (Wht), or both. These typically take the form of ca. 1 μm diameter spherules or >10 μm nodules and appear to be involved in the development and progression of age-related macular degeneration (AMD). Thus, these minerals may serve as useful biomarkers the for early detection and monitoring of sub-RPE changes in AMD. We demonstrated that HAP deposits could be imaged in vitro by fluorescence lifetime imaging microscopy (FLIM) in flat-mounted retinas using legacy tetracycline antibiotics as selective sensors for HAP. As the contrast on a FLIM image is based on the difference in fluorescence lifetime and not intensity of the tetracycline-stained HAP, distinguishing tissue autofluorescence from the background is significantly improved. The focus of the present pilot study was to assess whether vascular perfusion of the well tolerated and characterized chlortetracycline (widely used as an orally bioavailable antibiotic) can fluorescently label retinal HAP using human cadavers. We found that the tetracycline delivered through the peripheral circulation can indeed selectively label sub-RPE deposits opening the possibility for its use for ophthalmic monitoring of a range of diseases in which deposit formation is reported, such as AMD and Alzheimer disease (AD). Full article

(This article belongs to the Special Issue Ectopic Calcification in Hereditary and Acquired Diseases: From Bench to Bedside)

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9 pages, 899 KiB

Open AccessArticle

Lansoprazole Increases Inorganic Pyrophosphate in Patients with Pseudoxanthoma Elasticum: A Double-Blind, Randomized, Placebo-Controlled Crossover Trial

by Belén Murcia Casas, Juan Luis Carrillo Linares, Isabel Baquero Aranda, José Rioja Villodres, Vicente Merino Bohórquez, Andrés González Jiménez, Miguel Ángel Rico Corral, Ricardo Bosch, Miguel Ángel Sánchez Chaparro, María García Fernández and Pedro Valdivielso

Int. J. Mol. Sci. 2023, 24(5), 4899; https://doi.org/10.3390/ijms24054899 - 3 Mar 2023

Cited by 5 | Viewed by 2224

Abstract

Pseudoxanthoma elasticum (PXE) is characterized by low levels of inorganic pyrophosphate (PPi) and a high activity of tissue-nonspecific alkaline phosphatase (TNAP). Lansoprazole is a partial inhibitor of TNAP. The aim was to investigate whether lansoprazole increases plasma PPi levels in subjects with PXE. We conducted a 2 × 2 randomized, double-blind, placebo-controlled crossover trial in patients with PXE. Patients were allocated 30 mg/day of lansoprazole or a placebo in two sequences of 8 weeks. The primary outcome was the differences in plasma PPi levels between the placebo and lansoprazole phases. 29 patients were included in the study. There were eight drop-outs due to the pandemic lockdown after the first visit and one due to gastric intolerance, so twenty patients completed the trial. A generalized linear mixed model was used to evaluate the effect of lansoprazole. Overall, lansoprazole increased plasma PPi levels from 0.34 ± 0.10 µM to 0.41 ± 0.16 µM (p = 0.0302), with no statistically significant changes in TNAP activity. There were no important adverse events. 30 mg/day of lansoprazole was able to significantly increase plasma PPi in patients with PXE; despite this, the study should be replicated with a large number of participants in a multicenter trial, with a clinical end point as the primary outcome. Full article

(This article belongs to the Special Issue Ectopic Calcification in Hereditary and Acquired Diseases: From Bench to Bedside)

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14 pages, 2612 KiB

Open AccessArticle

p53 Regulates Mitochondrial Dynamics in Vascular Smooth Muscle Cell Calcification

by Kanchan Phadwal, Qi-Yu Tang, Ineke Luijten, Jin-Feng Zhao, Brendan Corcoran, Robert K. Semple, Ian G. Ganley and Vicky E. MacRae

Int. J. Mol. Sci. 2023, 24(2), 1643; https://doi.org/10.3390/ijms24021643 - 13 Jan 2023

Cited by 8 | Viewed by 3696

Abstract

Arterial calcification is an important characteristic of cardiovascular disease. It has key parallels with skeletal mineralization; however, the underlying cellular mechanisms responsible are not fully understood. Mitochondrial dynamics regulate both bone and vascular function. In this study, we therefore examined mitochondrial function in vascular smooth muscle cell (VSMC) calcification. Phosphate (Pi)-induced VSMC calcification was associated with elongated mitochondria (1.6-fold increase, p < 0.001), increased mitochondrial reactive oxygen species (ROS) production (1.83-fold increase, p < 0.001) and reduced mitophagy (9.6-fold decrease, p < 0.01). An increase in protein expression of optic atrophy protein 1 (OPA1; 2.1-fold increase, p < 0.05) and a converse decrease in expression of dynamin-related protein 1 (DRP1; 1.5-fold decrease, p < 0.05), two crucial proteins required for the mitochondrial fusion and fission process, respectively, were noted. Furthermore, the phosphorylation of DRP1 Ser637 was increased in the cytoplasm of calcified VSMCs (5.50-fold increase), suppressing mitochondrial translocation of DRP1. Additionally, calcified VSMCs showed enhanced expression of p53 (2.5-fold increase, p < 0.05) and β-galactosidase activity (1.8-fold increase, p < 0.001), the cellular senescence markers. siRNA-mediated p53 knockdown reduced calcium deposition (8.1-fold decrease, p < 0.01), mitochondrial length (3.0-fold decrease, p < 0.001) and β-galactosidase activity (2.6-fold decrease, p < 0.001), with concomitant mitophagy induction (3.1-fold increase, p < 0.05). Reduced OPA1 (4.1-fold decrease, p < 0.05) and increased DRP1 protein expression (2.6-fold increase, p < 0.05) with decreased phosphorylation of DRP1 Ser637 (3.20-fold decrease, p < 0.001) was also observed upon p53 knockdown in calcifying VSMCs. In summary, we demonstrate that VSMC calcification promotes notable mitochondrial elongation and cellular senescence via DRP1 phosphorylation. Furthermore, our work indicates that p53-induced mitochondrial fusion underpins cellular senescence by reducing mitochondrial function. Full article

(This article belongs to the Special Issue Ectopic Calcification in Hereditary and Acquired Diseases: From Bench to Bedside)

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Review

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13 pages, 1227 KiB

Open AccessReview

Zebrafish Models to Study Ectopic Calcification and Calcium-Associated Pathologies

by João M. A. Santos, Vincent Laizé, Paulo J. Gavaia, Natércia Conceição and M. Leonor Cancela

Int. J. Mol. Sci. 2023, 24(4), 3366; https://doi.org/10.3390/ijms24043366 - 8 Feb 2023

Cited by 4 | Viewed by 2973

Abstract

Ectopic calcification refers to the pathological accumulation of calcium ions in soft tissues and is often the result of a dysregulated action or disrupted function of proteins involved in extracellular matrix mineralization. While the mouse has traditionally been the go-to model organism for the study of pathologies associated with abnormal calcium deposition, many mouse mutants often have exacerbated phenotypes and die prematurely, limiting the understanding of the disease and the development of effective therapies. Since the mechanisms underlying ectopic calcification share some analogy with those of bone formation, the zebrafish (Danio rerio)—a well-established model for studying osteogenesis and mineralogenesis—has recently gained momentum as a model to study ectopic calcification disorders. In this review, we outline the mechanisms of ectopic mineralization in zebrafish, provide insights into zebrafish mutants that share phenotypic similarities with human pathological mineralization disorders, list the compounds capable of rescuing mutant phenotypes, and describe current methods to induce and characterize ectopic calcification in zebrafish. Full article

(This article belongs to the Special Issue Ectopic Calcification in Hereditary and Acquired Diseases: From Bench to Bedside)

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13 pages, 1045 KiB

Open AccessReview

Vascular Smooth Muscle Cell Neutral Sphingomyelinase 2 in the Release of Exosomes and Vascular Calcification

by Angelina Pavlic, Nasim Bahram Sangani, Johanna Kerins, Gerry Nicolaes, Leon Schurgers and Chris Reutelingsperger

Int. J. Mol. Sci. 2022, 23(16), 9178; https://doi.org/10.3390/ijms23169178 - 16 Aug 2022

Cited by 11 | Viewed by 3995

Abstract

Vascular calcification (VC) is the pathological precipitation of calcium salts in the walls of blood vessels. It is a risk factor for cardiovascular events and their associated mortality. VC can be observed in a variety of cardiovascular diseases and is most prominent in diseases that are associated with dysregulated mineral homeostasis such as in chronic kidney disease. Local factors and mechanisms underlying VC are still incompletely understood, but it is appreciated that VC is a multifactorial process in which vascular smooth muscle cells (VSMCs) play an important role. VSMCs participate in VC by releasing extracellular vesicles (EVs), the extent, composition, and propensity to calcify of which depend on VSMC phenotype and microenvironment. Currently, no targeted therapy is available to treat VC. In-depth knowledge of molecular players of EV release and the understanding of their mechanisms constitute a vital foundation for the design of pharmacological treatments to combat VC effectively. This review highlights our current knowledge of VSMCs in VC and focuses on the biogenesis of exosomes and the role of the neutral Sphingomyelinase 2 (nSMase2). Full article

(This article belongs to the Special Issue Ectopic Calcification in Hereditary and Acquired Diseases: From Bench to Bedside)

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