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 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Osteoprotegerin (OPG) and its ligand are cytokines that regulate osteoclastogenesis and that may be involved in the regulation of vascular calcification. We examined whether serum OPG levels were associated with stroke, mortality, and cardiovascular risk factors, including diabetes, as well as with bone mineral density and fractures in a sample of 490 participants in a prospective cohort of white women, at least 65 yr of age. We found that OPG levels, assayed blinded from serum obtained at baseline, were about 30% greater in women with diabetes (mean +/- SD, 0.30 +/- 0.17 ng/mL) than in those without diabetes (0.23 +/- 0.10 ng/mL; P = 0.0001). OPG levels were associated with all-cause mortality [age-adjusted odds ratio, 1.4/SD (0.11 ng/mL) increase in serum OPG level; 95% confidence interval, 1.2--1.8] and cardiovascular mortality (odds ratio, 1.4; 95% confidence interval, 1.1--1.8); these effects were not confounded by diabetes. OPG levels were not associated with baseline bone mineral density or with subsequent strokes or fractures. The association of serum OPG levels with diabetes and with cardiovascular mortality raises the possibility that OPG may be a cause of or a marker for vascular calcification.
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PMID:Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women. 1115 21

Vascular calcification is increasingly recognized as a significant contributor to cardiovascular morbidity and mortality as well as a biologically regulated process potentially subject to prevention and reversal. Both coronary and aortic calcification are common and influence plaque rupture, angioplasty and surgical complications, and compensatory enlargement. Aortic calcification increases aortic rigidity and contributes to cadiac ischemia, left ventricular hypertrophy, heart failure, and stroke. Calcification is also common in aortic valve leaflets further compounding adverse hemodynamic effects. Vascular calcification has often been attributed to "passive" crystallization. However, functional similarities between atherosclerotic lesions and bone contradict this view and indicate that it is no more "passive" than in embryonic bone formation or bone repair. Similarities include presence of all the major components of bone osteoid, bone regulatory factors, and subpopulations of artery wall cells that retain osteoblastic lineage potential. Several animal models for vascular calcification are available. Spontaneous vascular calcification occurs in null mice for matrix GLA protein (MGP), a small matrix protein of unknown function, and osteoprotegerin (OPG), known to modulate osteoclast differentiation. Vascular calcification may also be induced by feeding vitamin D and calcium or warfarin to normal animals, or by fat-feeding mice null for apoE or the LDL-receptor. Overall, regulation of vascular calcification is a growing field with surprising mechanisms and connections to other fields of biology.
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PMID:Regulatory mechanisms in vascular calcification. 1118 30

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.
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PMID:Osteogenic regulation of vascular calcification: an early perspective. 1510 15

In bone and teeth formation, coordinated calcification is a highly desirable biological process. However, heterotopic calcification at unwanted tissue sites leads to dysfunction, disease and, potentially, to death and therefore requires prevention and treatment. With the recent discovery of calcification inhibitors we now know that biological calcification is not passive but a complex, active and highly regulated process. Calcification at vascular sites is the most threatening localization and manifests as part of atherosclerosis or arteriosclerosis. Atherosclerosis is often accompanied by intimal plaque calcification, whereas arteriosclerosis is characterized by calcification of the media. The severity of calcification of cerebral or coronary atherosclerotic plaques is associated with an increased incidence of events such as stroke or myocardial infarction. Medial calcification is the major cause of arterial stiffness, which contributes to left ventricular dysfunction and heart failure. Patients with chronic kidney disease are at especially increased risk for both intimal and medial calcification. In this context, it is currently thought that calcium-regulatory factors including fetuin-A, matrix Gla protein, osteoprotegerin, and pyrophosphates act in a local or systemic manner to prevent calcifications of the vasculature, and that dys-regulations of such calcification inhibitors may contribute to progressive calcifications. Nephrolithiasis represents another process of unwanted calcification responsible for significant morbidity. More than 80% of renal stones contain calcium. Urinary factors inhibiting calcification are citrate, glycosaminoglycans, Tamm-Horsfall protein, and osteopontin. This review summarizes current experimental and clinical data underlining the biological importance of these calcification inhibitors.
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PMID:Inhibitors of calcification in blood and urine. 1737 84

Recent studies have indicated a link between bone metabolism and cardiovascular events in patients with chronic kidney disease (CKD). CKD is a major health problem worldwide. This study evaluates the role of noninvasive markers of bone metabolism in predicting cardiovascular morbidity (coronary artery disease, peripheral vascular disease, stroke) and mortality in patients with mild to severe forms of CKD. In a prospective cohort study, 627 patients with CKD were screened. To focus on bone metabolism, traditional risk factors for cardiovascular events were excluded, and 135 patients with CKD stages 1-5 were followed for 4 yr. Glomerular filtration rate was calculated by the Modification of Diet in Renal Disease formula. PTH (measured by four different assays), vitamin D 25 and 1,25, bone-specific alkaline phosphatase (BSALP), TRACP-5b, osteocalcin, serum collagen cross-link molecules, RANKL, and osteoprotegerin were determined. Predictors of cardiovascular events were evaluated by multivariable logistic regression, Kaplan-Meier survival, and Cox regression analysis. There were a total of 45 cardiovascular events (33%). Event rates were 5.6%, 29.1%, 45.2%, and 45.0% in CKD stages 1-2, 3, 4, and 5, respectively. In logistic regression, cardiovascular events were predicted only by (1) CKD stage (independent of age or sex; p < 0.001); (2) BSALP (p = 0.03); and (3) TRACP-5b (p = 0.04). Markers of bone formation (BSALP) and resorption (TRACP-5b) can serve as predictors of cardiovascular morbidity and mortality in CKD.
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PMID:Bone markers predict cardiovascular events in chronic kidney disease. 1859 36

The association of bone pathologies with atherosclerosis has stimulated the search for common mediators linking the skeletal and the vascular system. Since its initial discovery as a key regulator in bone metabolism, osteoprotegerin (OPG) has become the subject of intense interest for its role in vascular disease and calcification. Studies in vitro and in animal models suggest that OPG inhibits vascular calcification. Paradoxically however, clinical studies suggest that serum OPG levels increase in association with vascular calcification, coronary artery disease, stroke and future cardiovascular events. This has led to an extensive debate on the potential of OPG as a biomarker of vascular disease. However the exact significance and mechanisms by which this bone-regulatory protein influences cardiovascular pathophysiology is still unclear. The need for a more complete picture is being addressed in increasing valuable research indicating OPG as not only a marker but also a mediator of vascular pathology modulating osteogenic, inflammatory and apoptotic responses. By integrating the results of recent experimental research, animal models and clinical studies, this review summarises the present understanding of the role of OPG in vascular disease and calcification.
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PMID:Osteoprotegerin, vascular calcification and atherosclerosis. 1900 31

Extrarenal calcifications, particularly affecting the cardiovascular system, are common observations which can be a source of serious complications in patients with chronic renal disease, especially those on dialysis. In these patients, cardiovascular disease - myocardial infarction, arrhythmia, calcified valvulopathy, stroke, peripheral ischemic arteriopathy, calciphylaxy, etc. - is the leading cause of death (more than 50%). These complications are closely related to the presence of vascular calcifications (VC) which are much more frequent, severe, and progressive than in the general population. Previously, these calcifications were considered to arise via a passive process within the context of comorbid conditions without specific signs of gravity: high blood pressure, atherosclerosis, aging, diabetes, smoking, dyslipidemia, chronic micro-inflammation, hyperhomocysteinemia, disorders of calcium-phosphorus metabolism. It is now established that VC arise via a complex, probably regulated, active process analogous to the processes leading to bone formation and/or remodeling. New insight provided by a large body of work designed to ascertain the mechanisms underlying the onset of VC has enabled the development of new diagnostic and therapeutic approaches. It is now possible to identify factors clearly favoring the formation of VC: TNF-alpha (which stimulates cell necrosis/apoptosis), CRP, oxidized lipids, AGEs, leptin, inorganic phosphate, high calcium-phosphorus product (CaxPO(4)), calcium, 1,25-OH(2)D(3) and Vitamin D(3), PTHrP (via an intracrine pathway), cyclic AMP, TGF-beta, bone morphogenic protein 2 (BMP2) and factors protective against the formation of VC: magnesium, HDL, inorganic pyrophosphate, albumin, ahsg/fetuin A, osteopontin (OPN), osteoprotegerin (OPG), osteonectin (ON), bone morphogenic protein 7 (BMP7), klotho, PTHrP (via a paracrine pathway), matrix gla protein (MGP), PTH (via Msx2) and vitamin K. In conclusion, until recently, neglected disorders of calcium-phosphorus metabolism are currently recognized as the main actors in the process leading to vascular mediacalcosis in patients with chronic kidney failure.
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PMID:[Origin of the mediacalcosis in kidney failure]. 1934 26

Osteoprotegerin (OPG), a member of tumor necrosis factor receptor superfamily, has been implicated in vascular disease. We investigated the association of serum OPG with the ankle-brachial index (ABI) and urine albumin:creatinine ratio (UACR), in a bi-ethnic cohort of 1324 African-Americans (mean age 64 years, 71% women) and 1237 non-Hispanic whites (mean age 59 years, 57% women) belonging to hypertensive sibships. Serum levels of OPG were measured by solid phase sandwich immunoassay. ABI was measured using a standard protocol and peripheral arterial disease (PAD) defined as ABI<0.90. UACR was expressed as mg albumin/gm creatinine. Multivariable regression analysis using generalized estimating equations (GEE) were performed to assess whether serum OPG levels were associated with ABI and UACR. After adjustment for conventional risk factors (age, sex, diabetes, waist circumference, history of smoking, total and HDL cholesterol, hypertension), prior history of myocardial infarction or stroke, and medication (renin-angiotensin-aldosterone system inhibitors, statins, aspirin, estrogen) use, higher OPG levels were significantly associated with lower ABI and higher UACR in African-Americans (P=0.001 and P<0.0001, respectively) and non-Hispanic whites (P=0.017 and P=0.002, respectively); the association remained significant after further adjustment for plasma C-reactive protein (CRP) in both ethnic groups. In multivariable logistic regression analysis, higher OPG levels were associated with PAD in African-Americans, independent of the covariates listed above (P=0.026); the association remained significant after additional adjustment for plasma CRP (P=0.047). In non-Hispanic whites, the association of higher OPG levels with PAD was of borderline significance after adjustment for the relevant covariates (P=0.106). We conclude that higher OPG levels are associated with lower ABI and higher UACR, independent of conventional risk factors and plasma CRP.
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PMID:Association of serum osteoprotegerin with ankle-brachial index and urine albumin: creatinine ratio in African-Americans and non-Hispanic whites. 1942 12

This study investigated correlations between mortality, stroke subtype and stroke severity with serum osteoprotegerin (OPG) and S-100 protein levels prior to the treatment of patients admitted to the emergency department and diagnosed with ischaemic stroke. Pretreatment serum samples were collected from patients (n = 90) to determine OPG and S-100 protein levels. Age- and sex-matched healthy individuals (n = 16) served as controls. Compared with controls, OPG and S-100 protein levels were significantly higher in the cardioembolic and atherothrombotic stroke groups. Within the stroke group, OPG levels were significantly higher in the cardioembolic and atherothrombotic stroke groups compared with the transient ischaemic attack (TIA) group. S-100 protein levels were significantly higher in the atherothrombotic stroke group than in the lacunar stroke and TIA groups, and in the cardioembolic stroke group compared with the lacunar stroke group. Serum OPG and S-100 protein levels were significantly higher in patients who died compared with survivors. In predicting stroke subtype and severity, although both OPG and S-100 protein levels were indicators, S-100 protein was more valuable for mortality prediction.
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PMID:The role of serum osteoprotegerin and S-100 protein levels in patients with acute ischaemic stroke: determination of stroke subtype, severity and mortality. 2181 9

Atherosclerosis is the main cause of cardiovascular disease, but the extent of atherosclerosis in individual patients is difficult to estimate. A biomarker of the atherosclerotic burden would be very valuable. The aim of the present study was to evaluate the association of plasma osteoprotegerin (OPG) to clinical and subclinical atherosclerotic disease in a large community-based, cross-sectional population study. In the Copenhagen City Heart Study, OPG concentrations were measured in 5,863 men and women. A total of 494 participants had been hospitalized for ischemic heart disease or ischemic stroke, and compared to controls, this group with clinical atherosclerosis had higher mean OPG (1,773 vs 1,337 ng/L, p <0.001) and high-sensitivity C-reactive protein (2.3 vs 1.6 mg/L, p <0.001). In a multivariate model with age, gender, body mass index, hypertension, diabetes, hypercholesterolemia, smoking status, estimated glomerular filtration rate, high-sensitivity C-reactive protein, and OPG, OPG remained significantly associated with clinical atherosclerosis (p <0.01); high-sensitivity C-reactive protein, in contrast, did not (p = 0.74). In the control group without clinical atherosclerosis, OPG was independently associated with hypertension, diabetes, hypercholesterolemia, smoking, and subclinical peripheral atherosclerosis as measured by ankle brachial index. For each doubling of the plasma OPG concentration, the risk for subclinical peripheral atherosclerosis increased by 50% (p <0.001) after multivariate adjustment. In conclusion, OPG appears to be a promising biomarker of atherosclerosis that is independently associated with traditional risk factors of atherosclerosis, subclinical peripheral atherosclerosis, and clinical atherosclerotic disease such as ischemic heart disease and ischemic stroke.
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PMID:Comparison of osteoprotegerin to traditional atherosclerotic risk factors and high-sensitivity C-reactive protein for diagnosis of atherosclerosis. 2210 28


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