The osteoprotegerin/RANK/RANKL system: a bone key to vascular disease

Kiechl, Stefan; Werner, Philipp; Knoflach, Michael; Furtner, Martin; Willeit, Johann; Schett, Georg

doi:10.1586/14779072.4.6.801

Cited by 149 publications

(134 citation statements)

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“…In in vitro studies, osteoprotegerin was found to inhibit calcification in vascular smooth muscle cells70 and act as a survival factor in endothelial cells 71. In contrast, several lines of evidence from experimental studies in animals and cell cultures suggested harmful effects of osteoprotegerin in agreement with the positive association with CVD risk in our meta‐analysis 6. Osteoprotegerin not only contributes to systemic inflammation,72 but also to vasculature‐specific inflammation by increasing macrophage infiltration73 and leukocyte adhesion to endothelial cells 74, 75.…”

Section: Discussionsupporting

confidence: 86%

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Osteoprotegerin and Cardiovascular Events in High‐Risk Populations: Meta‐Analysis of 19 Prospective Studies Involving 27 450 Participants

Tschiderer

Klingenschmid

Nagrani

et al. 2018

JAHA

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BackgroundOsteoprotegerin is a cytokine involved in bone metabolism as well as vascular calcification and atherogenesis. Although circulating osteoprotegerin levels are robustly associated with incident cardiovascular disease (CVD) in the general population, its relevance as a biomarker among populations at high CVD risk is less clear.Methods and ResultsThree independent reviewers systematically searched PubMed, EMBASE, and Web of Science to identify prospective studies that had recruited participants on the basis of having conditions related to high CVD risk. A total of 19 studies were eligible for inclusion, reporting on 27 450 patients with diabetes mellitus (2 studies), kidney disease (7 studies), preexisting heart disease (5 studies), or recent acute coronary syndromes (5 studies) at baseline. Over a mean follow‐up of 4.2 years, 4066 CVD events were recorded. In a random‐effects meta‐analysis, the pooled risk ratio for CVD events comparing people in the top versus the bottom tertile of osteoprotegerin concentration was 1.30 (95% confidence interval, 1.12–1.50; P<0.001; I2=68.3%). There was evidence for presence of publication bias (P value from Egger's test=0.013). Correction for publication bias using the trim‐and‐fill method reduced the risk ratio to 1.21 (95% confidence interval, 1.03–1.42; P<0.001). The risk ratios did not vary significantly by population type, geographical region, statistical adjustment, sample or assay type, age, sex, or length of follow‐up.ConclusionsIn populations at high CVD risk, elevated circulating osteoprotegerin levels are associated with a higher risk for future CVD events. The magnitude of association appears weaker than in the general population.

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Section: Discussionsupporting

confidence: 86%

“…In addition to its role in bone homeostasis, osteoprotegerin has been implicated in the development of cardiovascular diseases (CVDs) 6. It is found in atherosclerotic plaques,7, 8 may regulate vascular calcification,9, 10 and may thereby influence cardiovascular risk.…”

Section: Introductionmentioning

confidence: 99%

Osteoprotegerin and Cardiovascular Events in High‐Risk Populations: Meta‐Analysis of 19 Prospective Studies Involving 27 450 Participants

Tschiderer

Klingenschmid

Nagrani

et al. 2018

JAHA

Self Cite

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“…Observational studies indicate that the level of soluble RANKL is lower in those on statin therapy than in those not on statin therapy. 26 Women taking statins have a higher bone density than those who do not. 52 In experimental rabbit aortic valve calcification, bone-matrix deposition is reduced by atorvastatin.…”

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confidence: 99%

The “Sunshine Deficit” and Cardiovascular Disease

2008

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I n past decades, the primary focus on vitamin D was the recognition and treatment of deficiency as it related to metabolic bone disease (rickets, osteomalacia, and secondary hyperparathyroidism). In the last 10 years, however, with the discovery of vitamin D receptors in multiple tissue types has come the recognition that the role of vitamin D extends beyond the musculoskeletal system. 1 The presence of abundant vitamin D receptors in myocardial tissue and vasculature and the observation that hypertension may be ameliorated with vitamin D suggest a greater role for vitamin D in the cardiovascular system. 2 Presently, large numbers of people are found to have hypovitaminosis D (a term chosen for this review to indicate any concentration below normal under substrate-saturated conditions) resulting in part from more indoor activities and the purposeful avoidance of sunshine. This review first describes why vitamin D, parathyroid hormone (PTH), and the skeleton are important to the heart and vasculature, then outlines why the epidemic of hypovitaminosis D deserves further scrutiny by the cardiovascular community, and finally suggests why treatment options for reducing hypovitaminosis D may favorably affect the morbidity and mortality of common cardiovascular disorders. Vitamin D and PTH: Basic Biochemistry and PhysiologyVitamin D is both a nutrient and a hormone. It is an essential precursor of calcitriol, 1,25-hydroxyvitamin D3 [1,25(OH) 2 D], which is necessary for bone development, growth, and mineralization and the maintenance of skeletal integrity. A cascade of steps is needed to cause progression of lesser active nutritionally ingested or synthesized vitamin D to more biologically active forms as depicted in Figure 1. 1 The cascade starts with the photolysis of 7 dehydrocholesterol in the epidermis by solar ultraviolet B (UVB) radiation to previtamin D3, which then undergoes thermal isomerization to vitamin D3. Vitamin D3 undergoes primary hydroxylation in the liver to 25-hydroxyvitamin D [25(OH)D] and then undergoes a second hydroxylation, primarily in the kidney, to the highly biologically active 1,25(OH) 2 D. Calcitriol increases bone resorption, gastrointestinal calcium absorption, renal tubular calcium reabsorption, and renal excretion of calcium. In concert with PTH, it is required for the efficient use of dietary calcium and the maintenance of calcium-phosphorus homeostasis, and it helps to maintain normal ionized calcium and phosphorus concentrations. PTH secretion is inversely related to ionized calcium concentration; thus, if the ionized calcium concentration drops, PTH secretion increases and restores normal calcium concentration. This is accomplished as the hormone stimulates renal production of calcitriol, increases osteoclastic bone resorption, increases gastrointestinal calcium absorption, and increases renal tubular resorption of calcium. PTH secretion is affected not only by vitamin D but also by disorders of magnesium and phosphorus metabolism, which may occur in conditions of malnutrition,...

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“…33,34 A previous study demonstrated both RANKL and OPG expression in nondiseased and early atherosclerosis. Interestingly, in calcified areas of advanced atherosclerotic lesions, OPG was expressed within the calcified areas with the RANKL in the areas surrounding them.…”

Section: Discussionmentioning

confidence: 98%