Osteogenic regulation of vascular calcification: an early perspective

2004 ◽  
Vol 286 (5) ◽  
pp. E686-E696 ◽  
Author(s):  
Radhika Vattikuti ◽  
Dwight A. Towler
Keyword(s):  
Parathyroid Hormone ◽  
Vascular Calcification ◽  
Current Data ◽  
Fracture Repair ◽  
Matrix Gla Protein ◽  
Bone Morphogenetic Protein 2 ◽  
Calcium Deposition ◽  
Variable Degree ◽  
Clinical Consequences ◽  
Stage Renal Disease

Cardiovascular calcification is a common consequence of aging, diabetes, hypercholesterolemia, mechanically abnormal valve function, and chronic renal insufficiency. Although vascular calcification may appear to be a uniform response to vascular insult, it is a heterogenous disorder, with overlapping yet distinct mechanisms of initiation and progression. A minimum of four histoanatomic variants—atherosclerotic (fibrotic) calcification, cardiac valve calcification, medial artery calcification, and vascular calciphylaxis—arise in response to metabolic, mechanical, infectious, and inflammatory injuries. Common to the first three variants is a variable degree of vascular infiltration by T cells and macrophages. Once thought benign, the deleterious clinical consequences of calcific vasculopathy are now becoming clear; stroke, amputation, ischemic heart disease, and increased mortality are portended by the anatomy and extent of calcific vasculopathy. Along with dystrophic calcium deposition in dying cells and lipoprotein deposits, active endochondral and intramembranous (nonendochondral) ossification processes contribute to vascular calcium load. Thus vascular calcification is subject to regulation by osteotropic hormones and skeletal morphogens in addition to key inhibitors of passive tissue mineralization. In response to oxidized lipids, inflammation, and mechanical injury, the microvascular smooth muscle cell becomes activated. Orthotopically, proliferating stromal myofibroblasts provide osteoprogenitors for skeletal growth and fracture repair; however, in valves and arteries, vascular myofibroblasts contribute to cardiovascular ossification. Current data suggest that paracrine signals are provided by bone morphogenetic protein-2, Wnts, parathyroid hormone-related polypeptide, osteopontin, osteoprotegerin, and matrix Gla protein, all entrained to endocrine, metabolic, inflammatory, and mechanical cues. In end-stage renal disease, a “perfect storm” of vascular calcification often occurs, with hyperglycemia, hyperphosphatemia, hypercholesterolemia, hypertension, parathyroid hormone resistance, and iatrogenic calcitriol excess contributing to severe calcific vasculopathy. This brief review recounts emerging themes in the pathobiology of vascular calcification and highlights some fundamental deficiencies in our understanding of vascular endocrinology and metabolism that are immediately relevant to human health and health care.

P0791MATRIX GLA PROTEIN AND PREMATURE VASCULAR CALCIFICATION IN PATIENTS WITH END-STAGE RENAL DISEASE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Lu Dai ◽  
Abdul Rashid Tony Qureshi ◽  
Jonaz Ripsweden ◽  
Torkel B Brismar ◽  
Magnus Söderberg ◽  
...  
Keyword(s):  
Renal Disease ◽  
Vascular Calcification ◽  
Vitamin K ◽  
End Stage Renal Disease ◽  
Protective Factor ◽  
Matrix Gla Protein ◽  
Vascular Aging ◽  
Dialysis Vintage ◽  
Stage Renal Disease ◽  
End Stage

Abstract Background and Aims Vitamin K is a potential protective factor against premature vascular aging and vascular calcification (VC). Whether vitamin K supplement could halt VC progression in patients with end-stage renal disease (ESRD) is not clear, partially due to the heterogeneity of measurements of VC in different vascular sites. Here we investigated the associations between non-phosphorylated, uncarboxylated matrix-Gla protein (dp-ucMGP), a circulating marker of vitamin K insufficiency, and premature vascular aging phenotypes evaluated by coronary artery calcium (CAC) scoring, aortic valve calcium (AVC) scoring, and histology scoring of presence of media calcification in vascular biopsies in patients with ESRD. Method In this observational cohort study, 223 ESRD patients (median age 54 years, 68% males) comprising non-dialysis patients (n=109), prevalent peritoneal dialysis (PD, n=80, median dialysis vintage 11.6 months) and prevalent hemodialysis patients (HD, n=34, median dialysis vintage 12.0 months) underwent baseline measurements of plasma dp-ucMGP and scoring of CAC and AVC by computed tomography scan. Framingham risk score (FRS), inflammation and other relevant clinical and biochemical data were determined at baseline. In a sub-group of patients (n=94), scoring of media calcification by histology in epigastric artery biopsies was also performed. Results Plasma dp-ucMGP levels (median 1568 pmol/L) significantly correlated with age (rho=0.38), presence of cardiovascular disease (CVD, rho=0.16), triglycerides (rho=0.19), FRS (rho=0.33), high-sensitivity C-reactive protein (hsCRP; rho=0.35), CAC score (rho=0.30) and AVC score (rho=0.24) but did not differ with regards to treatment modality (i.e. non-dialysis, PD and HD). In multivariate regression analyses, with adjustment for presence of CVD, FRS, hsCRP and triglycerides, increased dp-ucMGP levels were independently associated with increased CAC score (coefficients 0.12, p=0.04), but not with AVC score nor presence of media calcification in epigastric arteries. Conclusion Our data suggest that vitamin K insufficiency as indicated by increased dp-ucMGP levels associates with premature vascular calcification evaluated by CAC but not with AVC or media calcification assessed by histology. This discrepancy warrants further studies to explore the pathophysiological background between vitamin K metabolism and susceptibility of calcification in different vascular sites as well as the pattern of VC (i.e. intima and media calcification) within sites.

scholarly journals Role Of Vitamin K Therapy In Prevention Of Vascular Calcification In Chronic Kidney Disease

2020 ◽  
Vol 2 (4) ◽  
Author(s):  
Mohamed Farouk Ibrahim Mosa ◽  
Ahmed Kamal Harfoosh
Keyword(s):  
Vascular Calcification ◽  
Vitamin K ◽  
Vascular Wall ◽  
Matrix Gla Protein ◽  
Oral Vitamin ◽  
Inhibitory Protein ◽  
Baseline Levels ◽  
One Year ◽  
Stage Renal Disease ◽  
End Stage

Introduction: Matrix Gla protein (MGP) is a central calcification inhibitor of vascular wall. The biological activation of the calcification-inhibitory protein MGP can be achieved by simple administration of oral vitamin K. Aim: The study was conducted to assess the effect of vitamin k supplementation on vascular calcification and to evaluate its effect on MGA in hemodialysis patients. Materials and Methods: Forty adult patients with end stage renal disease (ESRD) on regular hemodialysis sessions, thrice weekly, were enrolled in the study and were randomly assigned into two groups. Vitamin K group consisted of 20 patients were given oral vitamin K at 10 mg after each session of dialysis for a duration of one year. No-Vitamin K group included 20 patients didn’t receive vitamin K. All patients were subjected to the following: Matrix Gla protein (MGP), in addition to, plain digital abdominal x-ray and doppler ultrasound. Results: After one-year of vitamin K supplementation, a significant increase in MGP levels in Vitamin K group (75.7±26 ng/mL) were noticed. There were no significant changes in CIMT and AACS in Vitamin K group after vitamin K supplementation in compared to their baseline levels, while the CIMT and AACS were significantly increased in No-Vitamin K group in compared to their baseline levels. Conclusion: Vitamin K supplementation could not stop vascular calcifications but significantly attenuate their progression.

scholarly journals Parathyroidectomy May Cause Remission of Uraemic Tumoral Calcinosis in Haemodialysis Patients

2022 ◽  
Author(s):  
Haiting Huang ◽  
Jun Lu ◽  
Pengwei Guo ◽  
Jun Pang ◽  
Jing Ma ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Parathyroid Hormone ◽  
Calcium Supplementation ◽  
Tumoral Calcinosis ◽  
Calcium Deposition ◽  
Intact Parathyroid Hormone ◽  
Metastatic Calcification ◽  
Significant Difference ◽  
The Masses ◽  
Stage Renal Disease

AbstractFew cases of uraemic tumoral calcinosis (UTC) have been reported. This study aimed to investigate the clinical efficacy of parathyroidectomy for UTC. Historical clinical data of patients with end-stage renal disease and UTC who underwent parathyroidectomy were analysed. Absorption of metastatic calcification was compared before and after operation. Changes in intact parathyroid hormone, serum calcium, phosphorus, and alkaline phosphatase levels were analysed before parathyroidectomy and at 1 week and 3, 6, and 12 months after parathyroidectomy. Eight patients met the enrolment criteria (men, 6; mean age, 38.6 SD 10.9 years). Uraemic tumoral calcinosis, which developed 2–8 years after dialysis began, was caused by secondary hyperparathyroidism. Massive calcium deposition was found in the shoulder (n = 6), hip (n = 3), and elbow (n = 2). Four patients had > 2 joints affected, and a single joint was involved for four patients. Seven patients had rapid remission (< 6 months) of the masses after parathyroidectomy. In one patient, the mass remained unabsorbed until 6 months postoperatively. Hypocalcaemia occurred in all patients where parathyroidectomy was successful, and calcium supplementation was required 1 year postoperatively. Serum intact parathyroid hormone levels on day 7 and at 3 and 6 months postoperatively decreased significantly from baseline and remained low 1 year postoperatively (22.015 SD33.134 pg/mL). Postoperative phosphorus levels were significantly lower than preoperative levels (p < 0.05), but no significant difference was found in alkaline phosphatase levels (p > 0.05). Parathyroidectomy has promising efficacy for UTC treatment and regulation of serum intact parathyroid hormone and phosphorus. Hypocalcaemia is a common complication after parathyroidectomy. Current Controlled Trials ChiCTR2000041311, date of registration: Dec. 23, 2020.

scholarly journals Roles of Nuclear Receptors in Vascular Calcification

2021 ◽  
Vol 22 (12) ◽  
pp. 6491
Author(s):  
Giulia Chinetti ◽  
Jaap G. Neels
Keyword(s):  
Nuclear Receptors ◽  
Vascular Calcification ◽  
Drug Targets ◽  
Target Genes ◽  
Soft Tissues ◽  
Vascular Wall ◽  
Calcium Deposition ◽  
Wall Calcification ◽  
Clinical Consequences

Vascular calcification is defined as an inappropriate accumulation of calcium depots occurring in soft tissues, including the vascular wall. Growing evidence suggests that vascular calcification is an actively regulated process, sharing similar mechanisms with bone formation, implicating both inhibitory and inducible factors, mediated by osteoclast-like and osteoblast-like cells, respectively. This process, which occurs in nearly all the arterial beds and in both the medial and intimal layers, mainly involves vascular smooth muscle cells. In the vascular wall, calcification can have different clinical consequences, depending on the pattern, localization and nature of calcium deposition. Nuclear receptors are transcription factors widely expressed, activated by specific ligands that control the expression of target genes involved in a multitude of pathophysiological processes, including metabolism, cancer, inflammation and cell differentiation. Some of them act as drug targets. In this review we describe and discuss the role of different nuclear receptors in the control of vascular calcification.

scholarly journals Fibroblast Growth Factor 21 Predicts and Promotes Vascular Calcification in Haemodialysis Patients

2020 ◽  
Author(s):  
Liqiong Jiang ◽  
Qing Yin ◽  
Min Yang ◽  
Min Li ◽  
Mingming Pan ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Thoracic Aorta ◽  
Vascular Calcification ◽  
Calcium Deposition ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Mineral Density ◽  
Mesenchymal Transition

Abstract Background: Cardiovascular disease (CVD) is the leading cause of death in haemodialysis (HD) patients. Vascular calcification (VC) is dramatically accelerated and is strongly associated with CVD events and mortality in HD patients. VC coexists with osteoporosis in many studies. Fibroblast growth factor 21 (FGF21) as an adipocytokines is a new hypoglycemic strategy and is inversely related to bone mineral density.Methods: To evaluate the contribution of FGF21 to VC in HD patients, we preliminary sreened 802 HD patients of two large HD centers in China. At last 388 HD patients were entered this cross-sectional study. We detected circulating FGF21 levels and measured the whole thoracic aorta calcification scores (TACS) and calcification scores of the three segments of thoracic aorta (TA), including ascending thoracic aorta (ATACS), aortic arch (AoACS), and descending thoracic aorta (DTACS) of our 388 HD patients. In addition, we pre-incubated human aortic endothelial cells (HAECs) with FGF21 in the presence or absence of parathyroid hormone (PTH) in vitro.Results: The median serum FGF21 level in HD patients was 11-fold higher than that in healthy controls. Ln(FGF21) was positively correlated with Ln(TACS+1), Ln(ATACS+1), Ln(AoACS+1) and Ln(DTACS+1) respectively in HD patients. Serum FGF21 was independently associated with TACS and ATACS, AoACS, and DTACS. FGF21 combined with age, calcium and intact parathyroid hormone demonstrated a high area under the curve (AUC=0.84) with optimal sensitivity (84%) and specificity (71%) for the prediction of VC in HD patients. Our vitro results showed that FGF21 enhanced the calcification effect of PTH on HAECs by increasing calcium deposition and endothelial-to-mesenchymal transition (EndMT).Conclusions: Circulating FGF21 was notably higher and was a potential predictor and promoter of VC in HD patients.Trial registration Chinese Clinical Trial Registry, identifier: ChiCTR1900028249. Registered 16 December 2019-Retrospectively registered,http://www.medresman.org.cn/uc/project/projectedit.aspx?proj=5981

scholarly journals Pro-calcifying analysis of uraemic serum from patients treated with medium cut-off membrane in a prospective, cross-over study

2020 ◽  
Author(s):  
Paola Ciceri ◽  
Giorgia Tettamanti ◽  
Andrea Galassi ◽  
Lorenza Magagnoli ◽  
Nicolas Fabresse ◽  
...  
Keyword(s):  
Osteoblastic Differentiation ◽  
Water Soluble ◽  
Matrix Gla Protein ◽  
Bone Morphogenetic Protein 2 ◽  
Calcium Deposition ◽  
Open Label ◽  
Small Water ◽  
Middle Molecules ◽  
Related Transcription Factor ◽  
The Difference

Abstract Background The retention of a large number of solutes that are normally excreted or metabolized by the kidney is responsible for the symptoms typical in uraemic patients. These molecules are defined as uraemic toxins and can be classified into three groups: small water-soluble molecules, middle molecules and protein-bound toxins. Recently, efforts were put towards developing dialysis membranes that allow the removal of large middle molecules without clinically relevant albumin loss. These membranes are the medium cut-off (MCO) membranes that allow the removal of middle molecules up to ∼50 000 Da. Methods We performed a prospective, open-label, controlled, cross-over pilot study comparing expanded haemodialysis (HDx) (novel MCO membrane Theranova 400) and conventional haemodialysis (HD) in 20 prevalent HD patients. Ten patients used conventional HD high-flux dialyser and 10 patients used HDx for 3 months; later the patients switched and received the other treatment for a further 3 months. We then analysed the pro-calcifying effect of uraemic serum in a model of high phosphate(Pi)–induced calcification in vascular smooth muscle cells (VSMCs). Results In this study, every patient was the control of himself and, interestingly, we found a tendency of less pro-calcifying potential from HDx-treated patients’ serum compared with HD. Studying pathogenetic processes involved in high Pi–induced calcium deposition, we found that uraemic serum of HDx-treated patients induced less VSMC necrosis compared with uraemic serum of HD patients. Nevertheless, no differences were found between the different dialytic treatments in the serum potential to induce apoptosis and to modulate the expression of a panel of genes involved in VSMC simil-osteoblastic differentiation such as bone morphogenetic protein 2, runt-related transcription factor 2, osteocalcin, matrix Gla protein, osteopontin, elastin and collagen I α1. In an effort to characterize the difference in uraemic toxin profile during the two different dialytic treatments, we measured a panel of 10 uraemic toxins and 3 precursors, finding a significant increased removal during HDx of 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, tryptophane and some of its metabolites, such as 3-indoxyl sulphate, indole 3-acetic acid and kynurenine. Conclusions These preliminary data are promising, although larger patients’ groups are needed to better understand the effects of HDx on vascular calcification.

Vitamin K for the Treatment of Cardiovascular Disease in End-Stage Renal Disease Patients: Is there Hope?

2020 ◽  
Vol 19 (1) ◽  
pp. 77-90 ◽  
Author(s):  
Stefanos Roumeliotis ◽  
Athanasios Roumeliotis ◽  
Evangelia Dounousi ◽  
Theodoros Eleftheriadis ◽  
Vassilios Liakopoulos
Keyword(s):  
Renal Disease ◽  
Vascular Calcification ◽  
Vitamin K ◽  
End Stage Renal Disease ◽  
Matrix Gla Protein ◽  
Ectopic Mineralization ◽  
Cv Disease ◽  
Stage Renal Disease ◽  
End Stage ◽  
Esrd Patients

In Chronic Kidney Disease, vascular calcification (VC) is highly prevalent even at early stages and is gradually enhanced, along with disease progression to End-Stage Renal Disease (ESRD). The calcification pattern in uremia includes all types of mineralization and contributes to the heavy cardiovascular (CV) burden that is common in these patients. Ectopic mineralization is the result of the imbalance between inhibitors and promoters of vascular calcification, with the latter overwhelming the former. The most powerful, natural inhibitor of calcification is Matrix Gla Protein (MGP), a small vitamin K dependent protein, secreted by chondrocytes and vascular smooth muscle cells. In uremia, MGP was reported as the only molecule able to reverse VC by “sweeping” calcium and hydroxyapatite crystals away from the arterial wall. To become biologically active, this protein needs to undergo carboxylation and phosphorylation, reactions highly dependent on vitamin K status. The inactive form of MGP reflects the deficiency of vitamin K and has been associated with CV events and mortality in ESRD patients. During the past decade, vitamin K status has emerged as a novel risk factor for vascular calcification and CV disease in various populations, including dialysis patients. This review presents evidence regarding the association between vitamin K and CV disease in ESRD patients, which are prone to atherosclerosis and atheromatosis.

scholarly journals Jacobsen syndrome and neonatal bleeding: report on two unrelated patients

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Gregorio Serra ◽  
Luigi Memo ◽  
Vincenzo Antona ◽  
Giovanni Corsello ◽  
Valentina Favero ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Comparative Genomic ◽  
Fish Analysis ◽  
Variable Degree ◽  
Jacobsen Syndrome ◽  
Contiguous Gene ◽  
Clinical Consequences ◽  
11Q Deletion

Abstract Introduction In 1973, Petrea Jacobsen described the first patient showing dysmorphic features, developmental delay and congenital heart disease (atrial and ventricular septal defect) associated to a 11q deletion, inherited from the father. Since then, more than 200 patients have been reported, and the chromosomal critical region responsible for this contiguous gene disorder has been identified. Patients’ presentation We report on two unrelated newborns observed in Italy affected by Jacobsen syndrome (JBS, also known as 11q23 deletion). Both patients presented prenatal and postnatal bleeding, growth and developmental delay, craniofacial dysmorphisms, multiple congenital anomalies, and pancytopenia of variable degree. Array comparative genomic hybridization (aCGH) identified a terminal deletion at 11q24.1-q25 of 12.5 Mb and 11 Mb, in Patient 1 and 2, respectively. Fluorescent in situ hybridization (FISH) analysis of the parents documented a de novo origin of the deletion for Patient 1; parents of Patient 2 refused further genetic investigations. Conclusions Present newborns show the full phenotype of JBS including thrombocytopenia, according to their wide 11q deletion size. Bleeding was particularly severe in one of them, leading to a cerebral hemorrhage. Our report highlights the relevance of early diagnosis, genetic counselling and careful management and follow-up of JBS patients, which may avoid severe clinical consequences and lower the mortality risk. It may provide further insights and a better characterization of JBS, suggesting new elements of the genotype-phenotype correlations.

scholarly journals Procyanidin B2 Reduces Vascular Calcification through Inactivation of ERK1/2-RUNX2 Pathway

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 916
Author(s):  
Yingquan Liang ◽  
Guilan Chen ◽  
Feng Zhang ◽  
Xiaoxiao Yang ◽  
Yuanli Chen ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Calcification ◽  
Aortic Root ◽  
Smooth Muscle Actin ◽  
Bone Morphogenetic Protein 2 ◽  
Plaque Burden ◽  
Runx2 Expression ◽  
Plaque Instability ◽  
Related Transcription Factor

Vascular calcification is strongly associated with atherosclerotic plaque burden and plaque instability. The activation of extracellular signal-regulated kinase 1/2 (ERK1/2) increases runt related transcription factor 2 (RUNX2) expression to promote vascular calcification. Procyanidin B2 (PB2), a potent antioxidant, can inhibit ERK1/2 activation in human aortic smooth muscle cells (HASMCs). However, the effects and involved mechanisms of PB2 on atherosclerotic calcification remain unknown. In current study, we fed apoE-deficient (apoE−/−) mice a high-fat diet (HFD) while treating the animals with PB2 for 18 weeks. At the end of the study, we collected blood and aorta samples to determine atherosclerosis and vascular calcification. We found PB2 treatment decreased lesions in en face aorta, thoracic, and abdominal aortas by 21.4, 24.6, and 33.5%, respectively, and reduced sinus lesions in the aortic root by 17.1%. PB2 also increased α-smooth muscle actin expression and collagen content in lesion areas. In the aortic root, PB2 reduced atherosclerotic calcification areas by 75.8%. In vitro, PB2 inhibited inorganic phosphate-induced osteogenesis in HASMCs and aortic rings. Mechanistically, the expression of bone morphogenetic protein 2 and RUNX2 were markedly downregulated by PB2 treatment. Additionally, PB2 inhibited ERK1/2 phosphorylation in the aortic root plaques of apoE−/− mice and calcified HASMCs. Reciprocally, the activation of ERK1/2 phosphorylation by C2-MEK1-mut or epidermal growth factor can partially restore the PB2-inhibited RUNX2 expression or HASMC calcification. In conclusion, our study demonstrates that PB2 inhibits vascular calcification through the inactivation of the ERK1/2-RUNX2 pathway. Our study also suggests that PB2 can be a potential option for vascular calcification treatment.

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