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Ectopic calcification (EC) of myofibers is a pathological feature of muscle damage in Duchenne muscular dystrophy (DMD). Mineralisation of muscle tissue occurs concomitantly with macrophage infiltration, suggesting a link between ectopic mineral deposition and inflammation. One potential link is the P2X7 purinoceptor, a key trigger of inflammation, which is expressed on macrophages but also up-regulated in dystrophic muscle cells. To investigate the role of P2X7 in dystrophic calcification, we utilised the Dmd mdx- βgeo dystrophin-null mouse model of DMD crossed with a global P2X7 knockout ( P2rx7 −/− ) or with our novel P2X7 knockin-knockout mouse ( P2x7 KiKo ), which expresses P2X7 in macrophages but not muscle cells. Total loss of P2X7 increased EC, indicating that P2X7 overexpression is a protective mechanism against dystrophic mineralisation. Given that muscle-specific P2X7 ablation did not affect dystrophic EC, this underlined the role of P2X7 receptor expression on the inflammatory cells. Serum phosphate reflected dystrophic calcification, with the highest serum phosphate levels found in genotypes with the most ectopic mineral. To further investigate the underlying mechanisms, we measured phosphate release from cells in vitro , and found that dystrophic myoblasts released less phosphate than non-dystrophic cells. Treatment with P2X7 antagonists increased phosphate release from both dystrophic and control myoblasts indicating that muscle cells are a potential source of secreted phosphate while macrophages protect against ectopic mineralisation. Treatment of cells with high phosphate media engendered mineral deposition, which was decreased in the presence of the P2X7 agonist BzATP, particularly in cultures of dystrophic cells, further supporting a protective role for P2X7 against ectopic mineralisation in dystrophic muscle.

Valve replacement is the main therapy for valvular heart disease, in which a diseased valve is replaced by mechanical heart valve (MHV) or bioprosthetic heart valve (BHV). Since the 2000s, BHV surpassed MHV as the leading option of prosthetic valve substitute because of its excellent hemocompatible and hemodynamic properties. However, BHV is apt to structural valve degeneration (SVD), resulting in limited durability. Calcification is the most frequent presentation and the core pathophysiological process of SVD. Understanding the basic mechanisms of BHV calcification is an essential prerequisite to address the limited-durability issues. In this narrative review, we provide a comprehensive summary about the mechanisms of BHV calcification on 1) composition and site of calcifications; 2) material-associated mechanisms; 3) host-associated mechanisms, including immune response and foreign body reaction, oxidative stress, metabolic disorder, and thrombosis. Strategies that target these mechanisms may be explored for novel drug therapy to prevent or delay BHV calcification.

Previous CKD-animal models primarily focused on a certain histological abnormality but lacked investigations of the interplay of EC in various tissues. This study compared calcified deposition in several tissues during CKD progression in mice, which was closely related. The severity of CKD was unparalleled with the development of ectopic calcification. Glomerular and tubular basement membrane calcification was detected in CKD mice, which has been considered extremely rare in clinical. Ectopic calcification (EC) involves multiple organ systems in chronic kidney disease (CKD). Previous CKD-animal models primarily focused on a certain histological abnormality but did not show the correlation with calcified development among various tissues. This study compared calcified deposition in various tissues during CKD progression in mice. Male 8-week-old C57BL/6J mice were randomly allocated to the seven groups: a basic, adenine, high-phosphorus, or adenine and high-phosphorus diet for 12-16 weeks (Ctl16, A12, P16, or AP16, respectively); an adenine diet for 4-6 weeks; and a high-phosphorus or adenine and high-phosphorus diet for 10-12 weeks (A6 + P10, A4 + P12, or A4 + AP12, respectively). Compared to the Ctl16 mice, the P16 mice only displayed a slight abnormality in serum calcium and phosphorus; the A12 mice had the most serious kidney impairment; the A4 + P12 and A6 + P10 mice had similar conditions of CKD, mineral abnormalities, and mild calcification in the kidney and aortic valves; the A4 + AP12 and AP16 groups had severe kidney impairment, mineral abnormalities and calcification in the kidneys, aortic valves and aortas. Furthermore, calcium-phosphate particles were deposited not only in the tubulointerstitial compartment but in the glomerular and tubular basement membrane. The elemental composition of EC in various tissues matched the calcification of human cardiovascular tissue as determined by energy dispersive spectroscopy. The severity of CKD was unparalleled with the progression of mineral metabolism disorder and EC. Calcification was closely related in different tissues and observed in the glomerular and tubular basement membranes.

Vascular calcifications are characterized by the ectopic deposition of calcium and phosphate in the vascular lumen or wall. They are a common finding in computed tomography scans or during autopsy and are often directly related to a pathological condition. While the pathogenesis and functional consequences of vascular calcifications have been intensively studied in some peripheral organs, vascular calcification and its pathogenesis in the central nervous system is poorly characterized and understood. Here, we review the occurrence of vessel calcifications in the brain in the context of aging and various brain diseases. We discuss the pathomechanism of brain vascular calcification in primary familial brain calcification as an example of brain vessel calcification. A particular focus is the response of microglia to the vessel calcification in the brain and their role in the clearance of calcifications.

We report a 64-year-old Japanese woman with a history of progressive loss of motor function and painful swelling of large joints. At the age of 54, profound calcification appeared around the shoulder and hip joints, which did not heal after repeated surgical resections. Iliac bone biopsy revealed osteomalacic changes. Laboratory data showed low serum alkaline phosphatase (ALP) activity and a high urine phosphoethanolamine (PEA) concentration with normal serum calcium, phosphate, and fibroblast growth factor 23 (FGF23) levels. Subsequent genetic analysis of the ALPL gene confirmed the diagnosis of hypophosphatasia (HPP) with the identification of a heterozygous single nucleotide deletion, c.1559delT (p.Leu520ArgfsX86). We started a mineral-targeted enzyme replacement therapy, asfotase alfa (AA), to treat the patient’s musculoskeletal symptoms. A follow-up bone biopsy after 12 months of AA treatment showed improvement of osteomalacia. Calcified deposits around the large joints were unchanged radiographically. To our knowledge, this is the first report of a patient with an adult-onset HPP who presented with profound calcification around multiple joints. Nonspecific clinical signs and symptoms in patients with adult-onset HPP often result in delayed diagnosis or misdiagnosis. We propose that bone biopsy and genetic analysis should be considered along with laboratory analysis for all patients with ectopic calcification around joints of unknown etiology for accurate diagnosis and better treatment.

[...]it is necessary to elucidate the molecular mechanism underlying ectopic calcification and to identify potential drugs to prevent its occurrence and progression. In the case of TAV, they viewed 18F-NaF PET/CT as a more accurate and valuable predictor of the hemodynamic progression of calcific AS.Niu et al.demonstrated that BMP type I receptor A (BMPR1A) participates in osteogenic differentiation and is a potential molecular target for preventing vascular calcification. [...]Pan et al.reviewed recent research progress on the relationship between various types of sirtuins and vascular calcification and concluded that once a deeper understanding of the sirtuin family is established, researchers will be able to identify the most effective therapeutic targets and develop clinically applicable drugs for the prevention and treatment of vascular calcification. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Pseudoxanthoma elasticum (PXE (OMIM 264800)) is an autosomal recessive connective tissue disorder mainly caused by mutations in the ABCC6 gene. PXE results in ectopic calcification primarily in the skin, eye and blood vessels that can lead to blindness, peripheral arterial disease and stroke. Previous studies found correlation between macroscopic skin involvement and severe ophthalmological and cardiovascular complications. This study aimed to investigate correlation between skin calcification and systemic involvement in PXE. Ex vivo nonlinear microscopy (NLM) imaging was performed on formalin fixed, deparaffinized, unstained skin sections to assess the extent of skin calcification. The area affected by calcification (CA) in the dermis and density of calcification (CD) was calculated. From CA and CD, calcification score (CS) was determined. The number of affected typical and nontypical skin sites were counted. Phenodex + scores were determined. The relationship between the ophthalmological, cerebro- and cardiovascular and other systemic complications and CA, CD and CS, respectively, and skin involvement were analyzed. Regression models were built for adjustment to age and sex. We found significant correlation of CA with the number of affected typical skin sites ( r  = 0.48), the Phenodex + score ( r  = 0.435), extent of vessel involvement ( V -score) ( r  = 0.434) and disease duration ( r  = 0.48). CD correlated significantly with V -score ( r  = 0.539). CA was significantly higher in patients with more severe eye ( p  = 0.04) and vascular ( p  = 0.005) complications. We found significantly higher CD in patients with higher V -score ( p  = 0.018), and with internal carotid artery hypoplasia ( p  = 0.045). Significant correlation was found between higher CA and the presence of macula atrophy ( β  = − 0.44, p  = 0.032) and acneiform skin changes ( β  = 0.40, p  = 0.047). Based on our results, the assessment of skin calcification pattern with nonlinear microscopy in PXE may be useful for clinicians to identify PXE patients who develop severe systemic complications.

Background Ectopic calcification, especially in soft tissues such as subcutaneous adipose tissue, is a rare and serious complication in chronic kidney disease (CKD) patients. It is commonly associated with cardiovascular morbidity and mortality. This case report highlights the occurrence of multiple ectopic calcifications in a patient with end-stage renal disease (ESRD) on peritoneal dialysis, emphasizing the role of inflammatory cytokines in the pathogenesis of this condition. Early and appropriate intervention can facilitate partial reversibility, highlighting the importance of regular follow-ups and the optimization of prescriptions, particularly in ensuring intensified high-quality, goal-oriented dialysis. Case presentation A 68-year-old female patient with diabetic nephropathy had been on maintenance peritoneal dialysis for four years. She presented with multiple subcutaneous nodules, particularly in the abdomen and lower limbs, for over a month. Ultrasound and non-contrast CT imaging revealed hyperechoic lesions and calcifications in the subcutaneous tissue, along with vascular and kidney calcifications. Laboratory results indicated inadequate dialysis, hypocalcemia, hyperphosphatemia, and significantly elevated serum parathyroid hormone (PTH) and inflammatory cytokines, including IL-6. The biopsy of the subcutaneous nodule from the lower abdomen revealed calcification and inflammation, accompanied by pronounced IL-6 expression. Treatment included intensified automated peritoneal dialysis (APD) combined with icodextrin peritoneal dialysis solution for long-term retention in the abdomen, cinacalcet, phosphate binders, calcitriol, and nutritional support. After one month, the patient’s condition showed significant improvement, with reduced calcification confirmed by follow-up ultrasound. Conclusions This case underscores the rarity of subcutaneous adipose tissue calcification in ESRD patients and highlights the crucial role of inflammatory factors, particularly IL-6, in the development of ectopic calcifications. Early, targeted interventions, especially high-quality, goal-directed dialysis, can significantly improve outcomes, illustrating the importance of regular monitoring and tailored treatment in preventing and managing calcification in CKD patients. Clinical trial number Not applicable.

Medial vascular calcification (MVC) is a degenerative process that involves the deposition of calcium in the arteries, with a high prevalence in chronic kidney disease (CKD), diabetes, and aging. Calcification is the process of precipitation largely of calcium phosphate, governed by the laws of thermodynamics that should be acknowledged in studies of this disease. Amorphous calcium phosphate (ACP) is the key constituent of early calcifications, mainly composed of Ca 2+ and PO 4 3– ions, which over time transform into hydroxyapatite (HAP) crystals. The supersaturation of ACP related to Ca 2+ and PO 4 3– activities establishes the risk of MVC, which can be modulated by the presence of promoter and inhibitor biomolecules. According to the thermodynamic parameters, the process of MVC implies: (i) an increase in Ca 2+ and PO 4 3– activities (rather than concentrations) exceeding the solubility product at the precipitating sites in the media; (ii) focally impaired equilibrium between promoter and inhibitor biomolecules; and (iii) the progression of HAP crystallization associated with nominal irreversibility of the process, even when the levels of Ca 2+ and PO 4 3– ions return to normal. Thus, physical-chemical processes in the media are fundamental to understanding MVC and represent the most critical factor for treatments’ considerations. Any pathogenetical proposal must therefore comply with the laws of thermodynamics and their expression within the medial layer.