Tissue Calcification in Normal and Pathological Environments

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: 31 May 2025 | Viewed by 11818

Special Issue Editor


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Guest Editor
Department of Medicine, Medical School, University of Udine, Udine, Italy
Interests: ectopic calcification; aortic valve bioprostheses; valve interstitial cells; tissue remodeling; fibrillar collagen

Special Issue Information

Dear Colleagues,

It is well known that physiological calcification is a regulated process occurring during histogenesis or the remodeling of the so-called hard tissues bones, bone-forming cartilages, tooth enamel, dentin, and cementum. The pathological calcific processes are associated with aging and/or various diseases and are usually classified into the main types referred to as dystrophic, metastatic, iatrogenic, idiopathic, and calciphylaxis, words which are not dictated by univocal and/or exhaustive criteria so that supernumerary adjectives are often used, such as endocrine, metabolic, vascular, infectious, congenital, or neoplastic. Thus, the common term “calcification” is actually consistent with its culmination in tissue mineralization but indeed indicating a composite ensemble of distinct processes, of which physiological calcification at most remains a reference model for better elucidating the ectopic mineralization processes occurring in soft tissues in terms of underlying molecular mechanisms and inherent stimulatory, inhibitory, and propagatory factors.

Because of the conflicting results gained hitherto, a debate is still ongoing as to whether ectopic calcification depends on osteogenic differentiation, rather than protein-dysregulated secretory processes or cell-death-based degenerative pathways, thereby the detection of therapeutics exclusively targeted to the suppression of osteogenic-like factors or their genes might be not entirely effective in treating this multifaceted and likely multifactorial disorder.

Bearing in mind that surgery remains the only viable solution to date, future investigation on calcification will have to continue in all directions employing multidisciplinary approaches and aiming to develop appropriate therapeutic strategies counteracting dysregulated calcification, so preventing or delaying the progression of a disorder that is increasingly recognized as a major health problem leading to relevant morbidity and mortality in humans of any age.

Given the great number of open problems and the complexity of the different calcific events, any investigation adding information on biomineralization in both normal and pathological contexts will be welcomed in the setting of the present Special Issue project.

I look forward to receiving your valuable contributions.

Dr. Fulvia Ortolani
Guest Editor

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Keywords

  • calcification
  • ectopic mineralization
  • bone
  • heterotopic ossification
  • calcium phosphate
  • calcium carbonate
  • calcium oxalate
  • procalcific cell death

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Published Papers (5 papers)

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Research

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24 pages, 13262 KiB  
Article
Placental Tissue Calcification and Its Molecular Pathways in Female Patients with Late-Onset Preeclampsia
by Miguel A. Ortega, Tatiana Pekarek, Diego De Leon-Oliva, Diego Liviu Boaru, Oscar Fraile-Martinez, Cielo García-Montero, Julia Bujan, Leonel Pekarek, Silvestra Barrena-Blázquez, Raquel Gragera, Patrocinio Rodríguez-Benitez, Mauricio Hernández-Fernández, Laura López-González, Raul Díaz-Pedrero, Ángel Asúnsolo, Melchor Álvarez-Mon, Natalio García-Honduvilla, Miguel A. Saez, Juan A. De León-Luis and Coral Bravo
Biomolecules 2024, 14(10), 1237; https://doi.org/10.3390/biom14101237 - 30 Sep 2024
Cited by 1 | Viewed by 1872
Abstract
Preeclampsia (PE) is a complex multisystem disease characterized by hypertension of sudden onset (>20 weeks’ gestation) coupled with the presence of at least one additional complication, such as proteinuria, maternal organ dysfunction, or uteroplacental dysfunction. Hypertensive states during pregnancy carry life-threatening risks for [...] Read more.
Preeclampsia (PE) is a complex multisystem disease characterized by hypertension of sudden onset (>20 weeks’ gestation) coupled with the presence of at least one additional complication, such as proteinuria, maternal organ dysfunction, or uteroplacental dysfunction. Hypertensive states during pregnancy carry life-threatening risks for both mother and baby. The pathogenesis of PE develops due to a dysfunctional placenta with aberrant architecture that releases factors contributing to endothelial dysfunction, an antiangiogenic state, increased oxidative stress, and maternal inflammatory responses. Previous studies have shown a correlation between grade 3 placental calcifications and an elevated risk of developing PE at term. However, little is known about the molecular pathways leading to placental calcification. In this work, we studied the gene and protein expression of c-Jun N-terminal kinase (JNK), Runt-related transcription factor 2 (RUNX2), osteocalcin (OSC), osteopontin (OSP), pigment epithelium-derived factor (PEDF), MSX-2/HOX8, SOX-9, WNT-1, and β-catenin in placental tissue from women with late-onset PE (LO-PE). In addition, we employed von Kossa staining to detect mineral deposits in placental tissues. Our results show a significant increase of all these components in placentas from women with LO-PE. Therefore, our study suggests that LO-PE may be associated with the activation of molecular pathways of placental calcification. These results could be the starting point for future research to describe the molecular mechanisms that promote placental calcification in PE and the development of therapeutic strategies directed against it. Full article
(This article belongs to the Special Issue Tissue Calcification in Normal and Pathological Environments)
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13 pages, 4009 KiB  
Article
Micro-Osteoperforations Accelerate Tooth Movement without Exacerbating the Progression of Root Resorption in Rats
by Tadasu Sugimori, Masaru Yamaguchi, Jun Kikuta, Mami Shimizu and Shinichi Negishi
Biomolecules 2024, 14(3), 300; https://doi.org/10.3390/biom14030300 - 2 Mar 2024
Cited by 1 | Viewed by 2244
Abstract
A recent study reported that micro-osteoperforations (MOPs) accelerated tooth movement by activating alveolar bone remodeling. However, very little is known about the relationship between MOPs and external apical root resorption during orthodontic treatment. In this study, in order to investigate the mechanism through [...] Read more.
A recent study reported that micro-osteoperforations (MOPs) accelerated tooth movement by activating alveolar bone remodeling. However, very little is known about the relationship between MOPs and external apical root resorption during orthodontic treatment. In this study, in order to investigate the mechanism through which MOPs accelerate tooth movement without exacerbating the progression of root resorption, we measured the volume of the resorbed root, and performed the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) method on exposed MOPs during experimental tooth movements in rats. Male Wistar rats (11 weeks old) were divided into three groups: 10 g orthodontic force (optimal force) applied to the maxillary first molar (optimal force: OF group), 50 g orthodontic force application (heavy force: HF group), and 10 g force application plus three small perforations of the cortical plate (OF + MOPs group). On days 1, 4, 7, 10, and 14 after force application, the tooth movement and root volume were investigated by micro-computed tomography. Furthermore, the number of apoptotic cells in the pressured sides of the periodontal ligament (PDL) and surrounding hard tissues were determined by TUNEL staining. The OF + MOPs group exhibited a 1.8-fold increase in tooth movement on days 7, 10, and 14 compared with the OF group. On days 14, the HF group had a higher volume of root loss than the OF and OF + MOPs groups. On the same day, the number of TUNEL-positive cells in the HF group increased at the root (cementum) site whereas that in the OF group increased at the alveolar bone site. Furthermore, the number of TUNEL-positive cells in the OF + MOPs group increased at the alveolar bone site compared with the OF group. These results suggest that MOPs accelerate orthodontic tooth movement without exacerbating the progression of root resorption. Full article
(This article belongs to the Special Issue Tissue Calcification in Normal and Pathological Environments)
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Review

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16 pages, 1461 KiB  
Review
Macrophages in Calcific Aortic Valve Disease: Paracrine and Juxtacrine Disease Drivers
by Polina Klauzen, Liubov Basovich, Daria Shishkova, Victoria Markova and Anna Malashicheva
Biomolecules 2024, 14(12), 1547; https://doi.org/10.3390/biom14121547 - 2 Dec 2024
Viewed by 1242
Abstract
A significant role in the pathogenesis of CAVD is played by innate immunity cells, such as macrophages. In stenotic valves, macrophages have enhanced inflammatory activity, and the population’s balance is shifted toward pro-inflammatory ones. Pro-inflammatory macrophages release cytokines, chemokines, and microRNA, which can [...] Read more.
A significant role in the pathogenesis of CAVD is played by innate immunity cells, such as macrophages. In stenotic valves, macrophages have enhanced inflammatory activity, and the population’s balance is shifted toward pro-inflammatory ones. Pro-inflammatory macrophages release cytokines, chemokines, and microRNA, which can directly affect the resident valvular cells and cause valve calcification. In CAVD patients, macrophages may have more pronounced pro-inflammatory properties, enhanced not only by paracrine signals but also by juxtacrine Notch signaling and epigenetic factors, which influence the maturation of macrophages’ progenitors. In this review, we observe the accumulated data on the involvement of macrophages in CAVD development via paracrine and juxtacrine interactions. Full article
(This article belongs to the Special Issue Tissue Calcification in Normal and Pathological Environments)
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21 pages, 795 KiB  
Review
Vascular Calcification: Molecular Networking, Pathological Implications and Translational Opportunities
by Miguel A. Ortega, Diego De Leon-Oliva, Maria José Gimeno-Longas, Diego Liviu Boaru, Oscar Fraile-Martinez, Cielo García-Montero, Amador Velazquez de Castro, Silvestra Barrena-Blázquez, Laura López-González, Silvia Amor, Natalio García-Honduvilla, Julia Buján, Luis G. Guijarro, Elisa Castillo-Ruiz, Miguel Ángel Álvarez-Mon, Agustin Albillos, Melchor Álvarez-Mon, Raul Diaz and Miguel A. Saez
Biomolecules 2024, 14(3), 275; https://doi.org/10.3390/biom14030275 - 25 Feb 2024
Cited by 11 | Viewed by 4345
Abstract
Calcification is a process of accumulation of calcium in tissues and deposition of calcium salts by the crystallization of PO43− and ionized calcium (Ca2+). It is a crucial process in the development of bones and teeth. However, pathological calcification [...] Read more.
Calcification is a process of accumulation of calcium in tissues and deposition of calcium salts by the crystallization of PO43− and ionized calcium (Ca2+). It is a crucial process in the development of bones and teeth. However, pathological calcification can occur in almost any soft tissue of the organism. The better studied is vascular calcification, where calcium salts can accumulate in the intima or medial layer or in aortic valves, and it is associated with higher mortality and cardiovascular events, including myocardial infarction, stroke, aortic and peripheral artery disease (PAD), and diabetes or chronic kidney disease (CKD), among others. The process involves an intricate interplay of different cellular components, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), fibroblasts, and pericytes, concurrent with the activation of several signaling pathways, calcium, Wnt, BMP/Smad, and Notch, and the regulation by different molecular mediators, growth factors (GFs), osteogenic factors and matrix vesicles (MVs). In the present review, we aim to explore the cellular players, molecular pathways, biomarkers, and clinical treatment strategies associated with vascular calcification to provide a current and comprehensive overview of the topic. Full article
(This article belongs to the Special Issue Tissue Calcification in Normal and Pathological Environments)
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Other

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12 pages, 2330 KiB  
Systematic Review
Unveiling the Hidden Burden: A Systematic Review on the Prevalence and Clinical Implications of Calcified Brain Metastases
by Alexandru Garaba, Pier Paolo Panciani, Aida Da’ana, Tamara Ius, Alessandro Tel, Marco Maria Fontanella, Marco Zeppieri, Fulvia Ortolani and Edoardo Agosti
Biomolecules 2024, 14(12), 1585; https://doi.org/10.3390/biom14121585 - 11 Dec 2024
Cited by 1 | Viewed by 1102
Abstract
Background: Brain calcifications, found in various conditions, may be incidental or crucial for diagnosis. They occur in physiological changes, infections, genetic diseases, neurodegenerative conditions, vascular syndromes, metabolic disorders, endocrine disorders, and primary tumors like oligodendroglioma. While often incidental, their presence can be vital [...] Read more.
Background: Brain calcifications, found in various conditions, may be incidental or crucial for diagnosis. They occur in physiological changes, infections, genetic diseases, neurodegenerative conditions, vascular syndromes, metabolic disorders, endocrine disorders, and primary tumors like oligodendroglioma. While often incidental, their presence can be vital for accurate diagnosis. Brain metastases are the most common neoplastic lesions in adults, with their incidence increasing due to improved diagnostic tools and overall oncologic patient survival. Calcifications within brain metastases are uncommon, mostly seen in patients treated with radiation therapy (RT). Although cases of calcified brain metastasis (CBM) are reported, large recent studies are scarce and the real incidence remains unclear. This lack of data raises the risk of underestimating CBM in the differential diagnosis of brain calcifications, potentially leading to misdiagnosis and delayed treatment, particularly when calcifications are observed without prior RT. Aim: This systematic review sought to assess the incidence of CBM in patients with identified primary tumors who underwent brain chemotherapy (CT) for staging. Additionally, the study aimed to explore the primary tumor types more frequently linked to CBM and determine whether CBM manifested initially or post-RT. Methods: A comprehensive search was performed across prominent medical databases (PubMed, Cochrane Library, and Embase) until 20 January 2024. The employed search method incorporated pertinent Medical Subject Headings (MeSH) and keywords such as “calcification”, “brain metastasis”, and “CT scan”. Studies included in this review were publications focusing on CBM in patients with identified primary tumors who underwent brain CT for staging. Results: In a systematic review of 39 studies on CBM in patients with identified primary tumors, 98 papers were initially identified, with 52 chosen for full-text analysis. Among them, 39 were deemed eligible after excluding 13 for various reasons. The study investigates brain calcifications in 1115 patients with metastatic disease, revealing that 7.89% had brain metastases, with 25% showing calcifications ab initio. These calcifications were more common than previously reported, emphasizing the need for attention to intraparenchymal brain calcifications in oncologic patients. Most CBM originated from lung and breast adenocarcinomas, and their correlation with primary tumor calcifications was inconclusive. Conclusions: The study highlights the significance of identifying evolving lesions in oncologic patients, calling for increased awareness among neuroradiologists and shedding light on the prevalence and characteristics of CBM. Full article
(This article belongs to the Special Issue Tissue Calcification in Normal and Pathological Environments)
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