Molecular mechanisms mediating vascular calcification: Role of matrix Gla protein (Review Article)

Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital (ACCI, Level 6), Cambridge, UK.
Nephrology (Impact Factor: 2.08). 11/2006; 11(5):455-61. DOI: 10.1111/j.1440-1797.2006.00660.x
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Patients with chronic kidney disease (CKD) have a higher incidence of vascular calcification and a greatly increased risk of cardiovascular death. The mechanisms involved in the accelerated vascular calcification observed in CKD have recently become clearer, leading to the hypothesis that a lack of natural inhibitors of calcification may trigger calcium deposition. One of these inhibitory factors, matrix Gla protein (MGP), is the focus of the present review. MGP, originally isolated from bone, is a vitamin K-dependent protein that is also highly expressed by vascular smooth muscle cells. MGP has been confirmed as a calcification-inhibitor in numerous studies; however, its mechanism of action is not completely understood. It potentially acts in several ways to regulate calcium deposition including: (i) binding calcium ions and crystals; (ii) antagonizing bone morphogenetic protein and altering cell differentiation; (iii) binding to extracellular matrix components; and (iv) regulating apoptosis. Its expression is regulated by several factors including retinoic acid, vitamin D and extracellular calcium ions, and a reduced form of vitamin K (KH2) is important in maintaining MGP in an active form. Therefore, strategies aimed at increasing its expression and activity may be beneficial in tipping the balance in favour of inhibition of calcification in CKD.

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    • "It is noteworthy that aging-related phenotypes seen in α-kl-/- mice are also very similar to many of the complications that develop in patients suffering from advanced-stage of chronic kidney diseases (CKD)1011121314. This similarity is further supported by evidence that (i) expression of α-kl mRNA and α-Kl protein is severely reduced in these patients15, (ii) high serum phosphate, the major cause of abnormalities of α-kl-/- mice, has been reported to be closely associated with high levels of cardiovascular disease morbidity and mortality in patients with CKD, particularly in patients with end-stage renal disease161718, and (iii) defects in FGF2319 and α-Kl1, together with dysregulation of endogenous anti-calcification factors such as matrix Gla protein, osteoprotegerin, carbonic anhydrase isoenzyme II, fibrillin-1, and fetuin-A20212223 are considered to play an important role in cardiovascular calcification, a dire complication of CKD. All these observations suggest that α-Kl and FGF23 are involved in the pathogeneses of not only aging-related syndromes, but also the complications of CKD. "
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    ABSTRACT: Taking good care of elderly is a major challenge of our society, and thus identification of potential drug targets to reduce age-associated disease burden is desirable. α-klotho(-/-) (α-kl) is a short-lived mouse model that displays multiple phenotypes resembling human aging-related syndromes. Such ageing phenotype of α-kl(-/-) mice is associated with activation of a proteolytic enzyme, Calpain-1. We hypothesized that uncontrolled activation of calpain-1 might be causing age-related phenotypes in α-kl-deficient mice. We found that daily administration of BDA-410, a calpain-1 inhibitor, strikingly ameliorated multiple aging-related phenotypes. Treated mice showed recovery of reproductive ability, increased body weight, reduced organ atrophy, and suppression of ectopic calcifications, bone mineral density reduction, pulmonary emphysema and senile atrophy of skin. We also observed ectopic expression of FGF23 in calcified arteries of α-kl(-/-) mice, which might account for the clinically observed association of increased FGF23 level with increased risk of cardiovascular mortality. These findings allow us to propose that modulation of calpain-1 activity is a potential therapeutic option for delaying age-associated organ pathology, particularly caused by the dysregulation of mineral ion homeostasis.
    Scientific Reports 08/2014; 4:5847. DOI:10.1038/srep05847 · 5.58 Impact Factor
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    • "Matrix Gla protein (MGP) is among the most important inhibitors of VC [11] [25]. Its effect on VC is mediated by inhibiting of calcium crystal formation, with binding surplus calcium ions or small crystals in tissues and clearing them from circulation [26] [27]. Data demonstrate that serum MGP concentrations in patients with calcification were lower in comparison to patients without calcification [28] [29]. "
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    ABSTRACT: Background Imbalanced Matrix Gla protein (MGP) and Osteoprotegerin (OPG) levels occur in inflammatory diseases. Aim of the work The aim of the present study was to evaluate serum MGP and OPG levels in Rheumatoid Arthritis (RA) patients and study their relation to the disease activity. Patients and methods Forty-five female RA patients and 45 age and sex-matched healthy controls were included in this study. Disease activity score 28-C-reactive protein (DAS28-CRP) was used for the assessment of disease activity. High-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), MGP and OPG were measured in patients and controls. The associations of MGP and OPG with DAS28-CRP and the other laboratory and clinical variables were analyzed. Results RA patients had significantly higher serum OPG levels (408.3 ± 520.9 pg/ml) and hs-CRP (2.8 ± 1.9 mg/l) than the control (92.5 ± 86.3 pg/ml and 0.9 ± 1.5 mg/l respectively) (p < 0.001 each). There was no significant difference in MGP levels between the patients and control (p = 0.3). The correlation of OPG and MGP with DAS28-CRP in the patients was insignificant (p = 0.4 and p = 0.8 respectively). Age positively correlated with OPG (r = 0.32, p = 0.02), but not with MGP concentration (r = 0.05, p = 0.64) in the RA patients. Conclusions The significant elevation of the OPG level in RA patients may through light on its possible role in the pathogenesis of this disease and could be considered as a future therapeutic target. The significant correlation with age suggests that OPG may be an important mediator especially in elderly RA cases.
    Egyptian Rheumatologist 07/2014; 36(3). DOI:10.1016/j.ejr.2014.01.003
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    • "BMP2 belongs to the TGF-β (transforming growth factor β) superfamily of growth factors and has been demonstrated playing a key role in the process of arterial calcification [19,20]. MGP, the vitamin K-dependent protein, binds to BMP2 and acts as an endogenous calcification inhibitor [21]. Since both the BMP2 and MGP participate in the process of arterial calcification, we observed the expressions of BMP2 and MGP in calcified radial arteries of hemodialysis patients. "
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    ABSTRACT: Background Arterial calcification is a significant cardiovascular risk factor in hemodialysis patients. A series of factors are involved in the process of arterial calcification; however, the relationship between malnutrition and arterial calcification is still unclear. Methods 68 hemodialysis patients were enrolled in this study. Nutrition status was evaluated using modified quantitative subjective global assessment (MQSGA). Related serum biochemical parameters were measured. And the radial artery samples were collected during the arteriovenous fistula surgeries. Hematoxylin/eosin stain was used to observe the arterial structures while Alizarin red stain to observe calcified depositions and classify calcified degree. The expressions of bone morphogenetic protein 2 (BMP2) and matrix Gla protein (MGP) were detected by immunohistochemistry and western blot methods. Results 66.18% hemodialysis patients were malnutrition. In hemodialysis patients, the calcified depositions were mainly located in the medial layer of the radial arteries and the expressions of BMP2 and MGP were both increased in the calcified areas. The levels of serum albumin were negatively associated with calcification score and the expressions of BMP2 and MGP. While MQSGA score, serum phosphorus and calcium × phosphorus product showed positive relationships with calcification score and the expressions of BMP2 and MGP. Conclusions Malnutrition is prevalent in hemodialysis patients and is associated with arterial calcification and the expressions of BMP2 and MGP in calcified radial arteries. Malnutrition may be a new inducer candidate for arterial calcification in hemodialysis patients.
    Journal of Translational Medicine 03/2013; 11(1):66. DOI:10.1186/1479-5876-11-66 · 3.93 Impact Factor
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