osteoprotegerin and Vascular-Diseases

Vascular calcification (VC) is highly prevalent in patients with chronic kidney disease (CKD) and is strongly associated with cardiovascular mortality and morbidity. Accumulating evidence over the past decade has challenged the hypothesis of close interaction between bone and VC what raises the possibility of a common underlying pathophysiological mechanism. Lately, bone regulatory proteins such as: osteoprotegerin (OPG) and Receptor Activator for Nuclear Factor κB Ligand (RANKL) has attracted attention of researchers as a possible key mediators of bone-vascular calcification imbalance. The literature search was carried out using the MEDLINE/PubMed database and a combination of keywords and MeSH terms, and only papers published since January 2005 to July 2016 were selected. The search resulted in 562 potential articles. After selection according to the eligibility criteria, 107 studies fulfilled were included (102 full texts and 5 was case reports). OPG and RANKL plays essential role in the regulation of bone metabolism and may be regarded as a possible link between VC, bone and mineral metabolism in CKD patients. Further studies are required to determine the diagnostic significance of these proteins in evaluation of progression and severity of VC process in CKD patients. Finally, the efficacy and safety, especially in regard to VC, of anti-RANKL therapy in CKD patients requires well-designed prospective, randomized trials.

Topics: Animals; Bone Diseases; Humans; Osteoprotegerin; RANK Ligand; Renal Insufficiency, Chronic; Vascular Diseases

Vascular calcification is highly associated with cardiovascular disease mortality, particularly in high-risk patients with diabetes and chronic kidney diseases (CKD). In blood vessels, intimal calcification is associated with atherosclerosis, whereas medial calcification is a nonocclusive process which leads to increased vascular stiffness and reduced vascular compliance. In the valves, calcification of the leaflets can change the mechanical properties of the tissue and result in stenosis. For many decades, vascular calcification has been noted as a consequence of aging. Studies now confirm that vascular calcification is an actively regulated process and shares many features with bone development and metabolism. This review provides an update on the mechanisms of vascular calcification including the emerging roles of the RANK/RANKL/OPG triad, osteoclasts, and microRNAs. Potential treatments adapted from osteoporosis and CKD treatments that are under investigation for preventing and/or regressing vascular calcification are also reviewed.

Topics: Animals; Antibodies, Monoclonal, Humanized; Atherosclerosis; Calcinosis; Calcium; Chelating Agents; Denosumab; Diphosphonates; Humans; Mice; MicroRNAs; Osteoclasts; Osteoporosis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Renal Insufficiency, Chronic; Teriparatide; Tunica Intima; Tunica Media; Vascular Calcification; Vascular Diseases

Over the last years our knowledge on the mechanisms involved in the pathogenesis of cardiovascular disease has been enriched by the discovery of new molecules emerging as novel risk factors. Osteoprotegerin (OPG) is a soluble glycoprotein, member of the tumor necrosis factor (TNF)-related superfamily, involved in bone resorption. It was first described as a key regulator of bone homeostasis and vascular calcification in mice. Clinical studies have suggested that serum OPG is associated with vascular calcification in humans. The role of OPG in the development of macroangiopathy in diabetes is not yet clear. It is possible that the increased OPG levels in diabetes reflect a compensatory response to arterial injury and that it is not involved in the pathogenesis of atherosclerosis. Whether harmful or not, determination of serum OPG levels has been suggested as a prognostic biomarker of cardiovascular disease. In addition, increased OPG levels have been reported in diabetic patients with microvascular complications. The potential of OPG administration for therapeutic reasons is challenging for future investigators. This review summarizes the current knowledge on the association between OPG and macrovascular as well microvascular complications of diabetes.

Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Vascular Diseases

Analysis of animal models is indispensable to elucidate the molecular mechanism in vascular calcification (VC) as well as to develop new therapies for VC. Various gene-modified mice that show VC have been reported, and considerable progress has been made through the analyses of these animals. Mice of which bone-calcification regulatory factors were modified are the representative animal models for VC, indicating that these factors certainly regulate VC as well as bone-calcification. Inducible VC in wild-type animals is also an important research tool for developing preventive and therapeutic approach for VC.

Topics: Animals; Animals, Genetically Modified; Bone Morphogenetic Protein 2; Calcinosis; Calcium-Binding Proteins; Disease Models, Animal; Extracellular Matrix Proteins; Matrix Gla Protein; Membrane Proteins; Mice; Osteoprotegerin; Phosphate Transport Proteins; Phosphoric Diester Hydrolases; Pyrophosphatases; Vascular Diseases

Vascular calcification often associates with bone-cartilage formation. Artery sclerotic lesions accompany the expression of bone matrix proteins such as osteopontin, osteocalcin and matrix Gla protein and transcription factors including Runx2, osterix and Sox9. These lesions also express BMP, osteoprotegerin (OPG) and RANKL, which are important factor regulating bone formation and resorption. MGP-deficient mice exhibited extensive artery calcification as well as OPG-deficient mice. Thus, bone metabolism-related factors actively participate in vascular calcification, which had been interpreted as a passive calcification due to dystrophic calcification.

Topics: Animals; Bone Morphogenetic Proteins; Calcinosis; Calcium-Binding Proteins; Cell Differentiation; Chondrocytes; Core Binding Factor Alpha 1 Subunit; Extracellular Matrix Proteins; Humans; Matrix Gla Protein; Mice; Osteoblasts; Osteocalcin; Osteogenesis; Osteopontin; Osteoprotegerin; RANK Ligand; Transcription Factors; Vascular Diseases

Osteoprotegerin (OPG) is a secreted glycoprotein central to bone turnover via its role as a decoy receptor for the receptor activator of nuclear factor kappaB ligand (RANKL) and has traditionally been linked to a number of bone-related diseases. However, there is additional evidence that OPG can promote cell survival by inhibiting TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. As a result, a number of in vitro, in vivo and clinical studies have been performed assessing the role of OPG in tumourigenesis. Similar studies have been performed regarding vascular pathologies, resulting from observations of expression and regulation of OPG in the vasculature. This review aims to provide an update on this area and assess the potential protective or detrimental role of OPG in both vascular pathologies and tumourigenesis.

Topics: Animals; Apoptosis; Bone and Bones; Bone Diseases; Cell Survival; Humans; Immune System; Neoplasms; Osteoprotegerin; RANK Ligand; TNF-Related Apoptosis-Inducing Ligand; Vascular Diseases

Cardiovascular disease is the leading cause of mortality in patients with end-stage renal disease (ESRD) and is attributed to a combination of traditional and non-traditional cardiovascular risk factors. In recent years, there has also been an increasing recognition of a very high prevalence of cardiovascular calcification in the ESRD population, including in patients receiving long-term peritoneal dialysis (PD). Numerous observational cohort studies have demonstrated the prognostic importance of cardiovascular calcifications in these patients. The mechanisms are not completely understood, but are likely multifactorial. The present article reviews the prevalence, clinical course, prognostic significance, and some contributing factors for vascular and valvular calcification in ESRD patients, including patients receiving PD therapy.

Topics: 1-Carboxyglutamic Acid; alpha-2-HS-Glycoprotein; Blood Proteins; Blood Vessels; C-Reactive Protein; Calcinosis; Calcium-Binding Proteins; Extracellular Matrix Proteins; Heart Valve Diseases; Heart Valves; Humans; Kidney Failure, Chronic; Matrix Gla Protein; Osteoprotegerin; Peritoneal Dialysis; Prevalence; Prognosis; Vascular Diseases

Osteoporosis and atherosclerosis are degenerative disorders of old age that often present together, but recently it has been suggested that the association between osteoporosis and cardio-vascular diseases is not just due to the aging process. The osteoprotegerin (OPG)/receptor activator of nuclear factor-kB (RANK)/RANK ligand (RANKL) system has been identified as a possible mediator of arterial calcification suggesting common links between osteoporosis and vascular diseases. Since the discovery of the OPG/RANK/RANKL system, much has been learned about its role in controlling skeletal biology; however, its role in the context of vascular biology is only beginning to be explored. It has been suggested that OPG might act as an autocrine/paracrine regulator of vascular calcification and might be useful as a serum marker of vascular disease. However, the exact role of OPG (or RANKL/RANK) in vascular calcification is still not completely understood. This review aims to report the recent findings on the relationship between osteoporosis and OPG/RANK/RANKL-mediated vascular disease.

Topics: Animals; Bone and Bones; Calcinosis; Humans; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction; Vascular Diseases

Experimental and clinical trials in the field of bone biology helped to clarify the role of receptors, which belong to the tumor necrosis factor family, such as osteoprotegerin and receptor activator of nuclear factor kappaB (RANK), in the regulation of bone remodeling. The ligand of the receptor activator of nuclear factor kappaB (RANKL) is a stimulator of bone resorption, while osteoprotegerin is the soluble "decoy" receptor to RANKL, protecting thereby bone from resorption. Pathological states of bone remodeling (like osteoporosis) are associated with imbalance in the activity of osteoprotegerin and the receptor activator of nuclear factor kappaB. Recent studies, however, also indicate that the osteoprotegerin/RANKL/RANK system has important roles in the regulation of the immune and vascular system as well. In this review we summarize the function and regulation of osteoprotegerin, its role in pathological states--primarily in cardiovascular diseases--and its relevance as a marker of cardiovascular risk. Finally, we present our prospective trial performed among the chronic dialyzed patients, where we examined the association between the cardiovascular mortality, osteoprotegerin levels and the arterial stiffness.

Topics: Aged; Analysis of Variance; Animals; Biomarkers; Blood Flow Velocity; Bone Diseases; Bone Remodeling; Calcinosis; Cardiovascular Diseases; Carotid Arteries; Female; Femoral Artery; Heart Rate; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Linear Models; Male; Middle Aged; Osteoprotegerin; Prospective Studies; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Renal Dialysis; Risk Assessment; Risk Factors; Time Factors; Vascular Diseases; Vascular Resistance; Vasodilation

The mortality rate is extremely high in chronic kidney disease (CKD), primarily due to the high prevalence of cardiovascular disease (CVD) in this patient group. Apart from traditional Framingham risk factors, evidences suggest that nontraditional risk factors, such as inflammation, oxidative stress, endothelial dysfunction, and vascular calcification also contribute to this extremely high risk of CVD. Disturbance in the mineral metabolism, especially in the ions of Ca and PO4, are linked to enhanced calcification of blood vessels. Although the mechanism(s) of this enhanced calcification process are not fully understood, current knowledge suggests that a large number (and an imbalance between them) of circulating promoters and inhibitors of the calcification process, that is, fetuin-A (or alpha 2-Heremans-Schmid glycoprotein, AHSG), matrix-Gla protein (MGP), osteoprotegerin (OPG), osteopontin (OPN), bone morphogenetic proteins (BMPs), and inorganic pyrophosphate (PPi), are involved in the deterioration of vascular tissue. Thus, an imbalance in these factors may contribute to the high prevalence of vascular complications in CKD patients. Among these mediators, studies on fetuin-A deserve further attention as clinical studies consistently show that fetuin-A deficiency is associated with vascular calcification, all-cause and cardiovascular mortality in CKD patients. Both chronic inflammation and the uremic milieu per se may contribute to fetuin-A depletion, as well as specific mutations in the AHSG gene. Recent experimental and clinical studies also suggest an intriguing link between fetuin-A, insulin resistance, and the metabolic syndrome.

Topics: alpha-2-HS-Glycoprotein; Blood Proteins; Bone Morphogenetic Protein 7; Calcinosis; Calcium-Binding Proteins; Cardiovascular Diseases; Chronic Disease; Extracellular Matrix Proteins; Humans; Inflammation; Kidney Diseases; Matrix Gla Protein; Metabolic Syndrome; Osteopontin; Osteoprotegerin; Vascular Diseases

Similarities in the mechanisms of vascular calcification and the processes of bone and cartilage mineralization have come to light in recent years. Although formerly thought to be an inactive process of hydroxyapatite crystal precipitation, presently, vascular calcification is considered a regulated type of tissue mineralization. Moreover, different pathways of tissue mineralization are discussed. Pathological types of calcification are correlated with aging, metabolic disorders, chronic low-grade inflammation, and with genetic and acquired dysregulation of inorganic pyrophosphate (PPi) metabolism. This chapter focuses on recent developments in understanding the mechanisms of vascular calcification with special emphasis on the particular calcification pathway and the impact of deficient inhibition of calcification.

Topics: alpha-2-HS-Glycoprotein; Animals; Arteries; Blood Proteins; Calcinosis; Calcium-Binding Proteins; Extracellular Matrix Proteins; Humans; Inflammation; Matrix Gla Protein; Osteopontin; Osteoprotegerin; Phosphoric Diester Hydrolases; Pyrophosphatases; Vascular Diseases

Increasing experimental evidence suggests that both tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and its soluble decoy receptor osteoprotegerin (OPG) are involved in vascular biology. In particular, emerging data indicate that recombinant soluble TRAIL may act as a molecule with potential anti-inflammatory activity in vascular physiopathology. Conversely, the presence of leukocytes expressing membrane-bound TRAIL in atherosclerotic lesions might be involved in the destabilization of atherosclerotic plaques by inducing apoptotic cell death of vascular smooth muscle cells in an inflammatory milieu. Also OPG seems to be involved in vascular homeostasis, by acting in a paracrine or autocrine manner as a survival factor for endothelial cells. However, an increased production of OPG may have a role in the development of vascular dysfunction likely by multiple potential mechanisms, not only related to its ability to neutralize TRAIL-activity but also mediated by its heparin-binding domain. In this review we have summarized and discussed both in vitro and in vivo data that suggest potential roles of TRAIL and OPG in vascular physiopathology. Further studies are needed to address how the TRAIL/OPG interaction, their reciprocal balance and/or interplay affect vascular biology in order to design innovative therapeutic strategies in vascular diseases.

Topics: Animals; Atherosclerosis; Endothelial Cells; Endothelium, Vascular; Gene Expression Regulation; Humans; Models, Biological; Osteoprotegerin; TNF-Related Apoptosis-Inducing Ligand; Vascular Diseases

In the last decade, the nephrology community has focused its attention on the main cause of morbidity and mortality in chronic renal failure patients: cardiovascular disease. In addition, recent studies pointed out that vascular calcification (VC) is a major cause of cardiovascular disease in the dialysis population. Interestingly, the pathogenesis of VC and soft tissue calcification in chronic kidney disease (CKD) has been extensively investigated. Nowadays we know that VC is associated not only with passive calcium phosphate deposition, but also with an active, cell-mediated process. To better understand the pathogenesis of VC in CKD, numerous regulatory proteins have been studied, because of their ability to inhibit mineral deposition in the vessels. We here examine the state of the art of those substances recognized as regulatory key factors in preventing VC in uremic conditions, such as fetuin A (alpha2-Heremans-Schmid glycoprotein), matrix gamma-carboxyglutamic acid protein, pyrophosphate, osteoprotegerin and bone morphogenetic protein. We conclude that at present it is too early to introduce these novel markers into clinical practice.

Topics: 1-Carboxyglutamic Acid; alpha-Fetoproteins; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcinosis; Diphosphates; Humans; Kidney Failure, Chronic; Models, Biological; Osteoprotegerin; Risk Factors; Transforming Growth Factor beta; Uremia; Vascular Diseases

Vascular calcification, a degenerative process considered in the past to be a passive procedure, has now been suggested to be related to ossification. Many proteins responsible for bone formation have been identified on the arterial wall. The OPG/RANKL/RANK axis, responsible for ossification and bone mineralization, seems to play a major role in vasculature and atherosclerosis. Mice lacking OPG gene present osteoporosis and arterial calcification, while overexpression of OPG gene leads to osteopetrosis. In the present review the latest knowledge related to the effects of the OPG/RANKL/RANK axis on vasculature, including atherosclerosis, will be analyzed. The clinical significance of circulating OPG and RANKL levels in vascular diseases will also be referred.

Topics: Animals; Calcinosis; Mice; Models, Biological; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Vascular Diseases

Atherosclerosis and vascular calcification often co-exist in chronic kidney disease (CKD) patients. Although the former has been recently recognized as an active inflammatory process, atherosclerosis-related calcification of the intima is still viewed as a passive epiphenomenon. Recent experimental data showed that ossification of the internal vascular wall might also be an active inflammatory process interrelated to atherosclerosis. Factors like RANKL (receptor activator of nuclear factor kappaB ligand), RANK and osteoprotegerin modulate vascular calcification and at the same time are involved in the process of atherosclerosis. Moreover, basic calcium phosphate crystals could interact with and activate monocytes-macrophages that produce proinflammatory cytokines capable of initiating - via endothelial activation and leukocyte adhesion - the atherosclerotic process. Thus, vascular calcification might be an active player and not simply an epiphenomenon in atherosclerosis. Should the above-mentioned data be confirmed in future studies, calcification of the internal vascular wall and atherosclerosis might be viewed and treated as tightly interconnected and linked by inflammation processes in CKD patients.

Topics: alpha-2-HS-Glycoprotein; Atherosclerosis; Blood Proteins; Calcinosis; Calcium Phosphates; Humans; Kidney Failure, Chronic; Lipoproteins, LDL; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Vascular Diseases

1997 saw the identification of a novel set of proteins within the tumor necrosis factor (TNF)/TNF receptor families that are required for the control of bone remodeling. Therefore, these receptors, receptor activator of nuclear factor kappa B (RANK), osteoprotegerin (OPG) and their ligand RANK ligand (RANKL) became the critical molecular triad controlling osteoclastogenesis and pathophysiologic bone remodeling. However, the establishment of the corresponding knock-out and transgenic mice revealed unexpected results, most particularly, the involvement of these factors in the vascular system and immunity. Thus, the OPG/RANK/RANKL molecular triad appears to be associated with vascular calcifications and plays a pivotal function in the development of the immune system through dendritic cells. OPG/RANK/RANKL thus constitute a molecular bridge spanning bone metabolism, vascular biology and immunity. This review summarizes recent knowledge of OPG/RANK/RANKL interactions and activities as well as the current evidence for their participation in osteoimmunology and vascular diseases. In fine, the targeting of the OPG/RANK/RANKL axis as novel therapeutic approaches will be discussed.

Topics: Animals; Bone and Bones; Humans; Mice; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Vascular Diseases

Vascular calcification is often encountered in advanced atherosclerotic lesions and is a common consequence of aging. Calcification of the coronary arteries has been positively correlated with coronary atherosclerotic plaque burden, increased risk of myocardial infarction, and plaque instability. Chronic kidney disease (CKD) patients have two to five times more coronary artery calcification than healthy age-matched individuals. Vascular calcification is a strong prognostic marker of cardiovascular disease mortality in CKD patients. Vascular calcification has long been considered to be a passive, degenerative, and end-stage process of atherosclerosis and inflammation. However, recent evidence indicates that bone matrix proteins such as osteopontin, matrix Gla protein (MGP), and osteocalcin are expressed in calcified atherosclerotic lesions, and that calcium-regulating hormones such as vitamin D3 and parathyroid hormone-related protein regulate vascular calcification in in vitro vascular calcification models based on cultured aortic smooth muscle cells. These findings suggest that vascular calcification is an actively regulated process similar to osteogenesis, and that bone-associated proteins may be involved in the development of vascular calcification. The pathogenesis of vascular calcification in CKD is not well understood and is almost multifactorial. In CKD patients, several studies have found associations of both traditional risk factors, such as hypertension, hyperlipidemia, and diabetes, and uremic-specific risk factors with vascular calcification. Most patients with progressive CKD develop hyperphosphatemia. An elevated phosphate level is an important risk factor for the development of calcification and cardiovascular mortality in CKD patients. Thus, it is hypothesized that an important regulator of vascular calcification is the level of inorganic phosphate. In order to test this hypothesis, we characterized the response of human smooth muscle cell (HSMC) cultures to inorganic phosphate levels. Our findings indicate that inorganic phosphate directly regulates HSMC calcification through a sodium-dependent phosphate transporter mechanism. After treatment with elevated phosphate, there is a loss of smooth muscle lineage markers, such as alpha-actin and SM-22alpha, and a simultaneous gain of osteogenic markers such as cbfa-1 and osteocalcin. Elevated phosphate may directly stimulate HSMC to undergo phenotypic changes that predispose to calcification, a

Topics: Alkaline Phosphatase; Bone and Bones; Calcification, Physiologic; Calcium; Calcium-Binding Proteins; Cell Differentiation; Disease Progression; Extracellular Matrix Proteins; Glycoproteins; Humans; Kidney Failure, Chronic; Matrix Gla Protein; Models, Biological; Osteoblasts; Osteoprotegerin; Phosphates; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk Factors; Vascular Diseases

TRAIL is a member of the tumor necrosis factor superfamily that interacts with an unusually complex receptor system, comprising transmembrane (TRAIL-R1, -R2, -R3 and -R4) and soluble (osteoprotegerin) receptors. TRAIL has received considerable attention because of the finding that many cancer cell types are sensitive to TRAIL-induced apoptosis. However, increasing experimental evidence shows that TRAIL exhibits regulatory roles in various normal tissues, as well. Although the best-characterized biological activity of TRAIL is in the homeostatic regulation of the immune system, in this review we have summarized and discussed the physiological function of TRAIL and its receptors, in normal hematopoiesis and vascular physiopathology.

Topics: Animals; Apoptosis Regulatory Proteins; Endothelium, Vascular; Erythropoiesis; Glycoproteins; Hematopoiesis; Humans; Megakaryocytes; Membrane Glycoproteins; Mice; Monocytes; Neoplasms; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha; Vascular Diseases

Vascular calcification significantly impairs cardiovascular physiology, and its mechanism is under investigation. Many of the same factors that modulate bone osteogenesis, including cytokines, hormones, and lipids, also modulate vascular calcification, acting through many of the same transcription factors. In some cases, such as for lipids and cytokines, the net effect on calcification is positive in the artery wall and negative in bone. The mechanism for this reciprocal relation is not established. A recent series of reports points to the possibility that two bone regulatory factors, receptor activator of NF-kappaB ligand (RANKL) and its soluble decoy receptor, osteoprotegerin (OPG), govern vascular calcification and may explain the phenomenon. Both RANKL and OPG are widely accepted as the final common pathway for most factors and processes affecting bone resorption. Binding of RANKL to its cognate receptor RANK induces NF-kappaB signaling, which stimulates osteoclastic differentiation in preosteoclasts and induces bone morphogenetic protein (BMP-2) expression in chondrocytes. A role for RANKL and its receptors in vascular calcification is spported by several findings: a vascular calcification phenotype in mice genetically deficient in OPG; an increase in expression of RANKL, and a decrease in expression of OPG, in calcified arteries; clinical associations between coronary disease and serum OPG and RANKL levels; and RANKL induction of calcification and osteoblastic differentiation in valvular myofibroblasts.

Topics: Animals; Atherosclerosis; Calcinosis; Humans; Osteogenesis; Osteoprotegerin; RANK Ligand; TNF-Related Apoptosis-Inducing Ligand; Vascular Diseases

Owing to the common coincidence of osteoporosis and vascular disease, pathophysiological links between both disorders have long been sought. The osteoprotegerin (OPG)/receptor activator of NF-kappaB (RANK)/receptor activator of NF-kappaB ligand (RANKL) cytokine network, a key regulatory system in bone homeostasis, has been implicated recently in vascular calcification, changes in matrix composition and diabetic macroangiopathy, aortic aneurysm development, heart failure and, most importantly, advanced atherosclerosis, plaque destabilization and manifestation of cardiovascular diseases. The concept of an active role of RANKL and OPG in vascular pathophysiology is intriguing and is gaining increasing support from both epidemiological and basic research. OPG serum level is considered to be a stable and reliable indicator of the overall activity of the OPG/RANK/RANKL axis and may find application as a biomarker of vascular risk and prognosis. RANKL in turn may be a suitable target for novel therapies. Pharmacological strategies for specific interference with the OPG/RANK/RANKL axis are currently being developed and evaluated in osteoporosis therapy.

Topics: Biomarkers; Bone Remodeling; Humans; Osteoporosis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Vascular Diseases

The discovery of the receptor activator for nuclear factor kappaB (RANK) ligand (RANKL)/RANK signaling pathway has marked a major advance in our understanding of the mechanisms controlling osteoclastogenesis. RANKL, expressed by preosteoblasts and stromal cells, binds to RANK, expressed by cells of the osteoclast lineage, inducing a signaling cascade leading to the differentiation and fusion of osteoclast precursor cells and stimulating the activity of the mature osteoclast. The effects of RANKL are counteracted by osteoprotegerin (OPG), a soluble neutralizing decoy receptor.. This paper reviews the literature surrounding the use of circulating OPG and soluble RANKL (sRANKL) measurements and assesses their potential as markers of bone disease. Original clinical and basic research articles and reviews were identified using a Pubmed search strategy (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) and cover the time period up until January 2005. Search terms osteoprotegerin, OPG, RANK, RANKL, and RANK ligand were used alone and in combination with bone, osteoporosis, and disease.. Assays for detecting OPG and sRANKL in the circulation in humans have been developed, and differences in the circulating concentrations of OPG and sRANKL have been observed in different disease states. There are, however, some inconsistencies in study outcome. These may relate to differences in study design, methodology, and other unknown factors influencing the variability of these measurements.. The clinical utility of serum OPG and sRANKL measurements as markers of disease activity requires additional investigation. In particular, rigorous testing of assays and identification of the sources of measurement variability are required.

Topics: Bone Diseases, Metabolic; Carrier Proteins; Female; Fracture Healing; Glycoproteins; Humans; Male; Membrane Glycoproteins; Neoplasms; Osteoporosis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Sex Factors; Vascular Diseases

The clinical coincidence of osteoporosis and vascular disease has long indicated that common mediators may adversely affect bone metabolism and vascular integrity alike. Receptor activator of NF-kappaB ligand (RANKL) is an important cytokine for bone resorption that acts through its osteoclastic receptor, receptor activator of NF-kappaB (RANK), while osteoprotegerin serves as a decoy receptor that binds RANKL and prevents activation of RANK. Skeletal and vascular cells are sources and targets of RANKL and OPG both in vitro and in vivo. Modulation of the RANKL/RANK/OPG system in animals results in a skeletal and vascular phenotype, and administration of OPG may prevent osteoporosis and vascular calcification. Recent studies on OPG serum levels and gene polymorphisms also suggest an important role of this cytokine system in skeletal and vascular diseases. In summary, there is increasing evidence that RANKL and OPG may link the skeletal with the vascular system.

Topics: Animals; Carrier Proteins; Glycoproteins; Humans; Membrane Glycoproteins; Models, Biological; Osteoporosis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vascular Diseases

This review focuses on the impact of a recent breakthrough in bone cell biology for understanding the pathophysiology of bone/vascular abnormalities associated with uraemia.. Osteoprotegerin is a humoral osteoclastogenesis/osteoclast activation inhibitory factor, which belongs to the TNF-alpha receptor superfamily. Serum osteoprotegerin levels are elevated along with the deterioration of the glomerular filtration rate. The circulating osteoprotegerin molecules were likely to preserve the activity of osteoclastogenesis inhibition, and the levels in many dialysis patients were high enough to inhibit osteoclastogenesis. The higher serum osteoprotegerin levels were related to the development of vascular calcification.. Osteoprotegerin is a potential uraemic toxin that increases the skeletal resistance to PTH. However, the roles of increased circulating osteoprotegerin on bone and/or vascular abnormalities in uraemia remain to be clarified.

Topics: Bone and Bones; Bone Density; Bone Diseases; Glycoproteins; Humans; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Insufficiency; Uremia; Vascular Diseases

Bone resorption by osteoclasts is coupled with bone formation by osteoblasts, and this balanced process continuously remodels and adapts the skeleton. The receptor activator of nuclear factor kappaB ligand (RANKL) has been identified as an essential cytokine for the formation and activation of osteoclasts. The effects of RANKL are physiologically counterbalanced by the decoy receptor osteoprotegerin (OPG). Estrogen deficiency, glucocorticoid exposure, T-cell activation (eg, rheumatoid arthritis), and skeletal malignancies (eg, myeloma, metastases) enhance the ratio of RANKL to OPG and, thus, promote osteoclastogenesis, accelerate bone resorption, and induce bone loss. Moreover, alterations of the OPG/RANKL/RANK system have been implicated in vascular diseases. RANKL blockade (using OPG or RANK fusion proteins or RANKL antibodies) has prevented bone loss caused by osteoporosis, chronic inflammatory disorders, and malignant tumors in animal models and may emerge as a therapy in humans based on studies in postmenopausal osteoporosis, myeloma bone disease, and osteolytic metastases. This review summarizes the clinical implications of the OPG/RANKL/RANK system for bone and vascular diseases.

Topics: Animals; Antibodies, Monoclonal; Bone Diseases; Bone Remodeling; Bone Resorption; Carrier Proteins; Glycoproteins; Humans; Ligands; Membrane Glycoproteins; Osteoclasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Recombinant Proteins; Vascular Diseases

Vascular calcification often occurs with advancing age, atherosclerosis, various metabolic disorders such as diabetes mellitus and end-stage renal disease, or in rare genetic diseases, leading to serious clinical consequences. Such mineralization can occur at various sites (cardiac valves, arterial intima or media, capillaries), involve localized or diffuse widespread calcification, and result from numerous causes that provoke active inflammatory and osteogenic processes or disordered mineral homeostasis. Although valuable research has defined many key factors and cell types involved, surprising new insights continue to arise that deepen our understanding and suggest novel research directions or strategies for clinical intervention in calcific vasculopathies. One emerging area in vascular biology involves the RANKL/RANK/OPG system, molecules of the tumor necrosis factor-related family recently discovered to be critical regulators of immune and skeletal biology. Evidence is accumulating that such signals may be expressed, regulated, and function in vascular physiology and pathology in unique ways to promote endothelial cell survival, angiogenesis, monocyte or endothelial cell recruitment, and smooth muscle cell osteogenesis and calcification. Concerted research efforts are greatly needed to understand these potential roles, clarify whether RANKL (receptor activator of nuclear factor kappaB ligand) promotes and osteoprotegerin (OPG) protects against vascular calcification, define how OPG genetic polymorphisms relate to cardiovascular disease, and learn whether elevated serum OPG levels reflect endothelial dysfunction in patients. Overall, the RANKL/RANK/OPG system may mediate important and complex links between the vascular, skeletal, and immune systems. Thus, these molecules may play a central role in regulating the development of vascular calcification coincident with declines in skeletal mineralization with age, osteoporosis, or disease.

Topics: Animals; Arteriosclerosis; Bone and Bones; Calcinosis; Carrier Proteins; Endothelium, Vascular; Glycoproteins; Humans; Immune System; Membrane Glycoproteins; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Osteoclasts; Osteoporosis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vascular Diseases

In 1997, investigators isolated a secreted glycoprotein that blocked osteoclast differentiation from precursor cells, prevented osteoporosis (decreased bone mass) when administered to ovariectomized rats, and resulted in osteopetrosis (increased bone mass) when overexpressed in transgenic mice. Since then, the isolation and characterization of the protein named osteoprotegerin (OPG) has stimulated much work in the fields of endocrinology, rheumatology, and immunology. OPG functions as a soluble decoy receptor for receptor activator of nuclear factor-kappaB ligand (RANKL, or OPG ligand) and shares homologies with other members of the tumor necrosis factor receptor superfamily. OPG acts by competing with the receptor activator of nuclear factor-kappaB, which is expressed on osteoclasts and dendritic cells for specifically binding to RANKL. RANKL is crucially involved in osteoclast functions and bone remodeling as well as immune cell cross-talks, dendritic cell survival, and lymph node organogenesis. More recently, emerging evidence from in vitro studies and mouse genetics attributed OPG an important role in vascular biology. In fact, OPG could represent the long sought-after molecular link between arterial calcification and bone resorption, which underlies the clinical coincidence of vascular disease and osteoporosis, which are most prevalent in postmenopausal women and elderly people.

Topics: Animals; Arteries; Bone and Bones; Bone Remodeling; Bone Resorption; Calcinosis; Carrier Proteins; Glycoproteins; Humans; Membrane Glycoproteins; Mice; Osteopetrosis; Osteoporosis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vascular Diseases

Topics: Animals; Arteries; Arteriosclerosis; Calcinosis; Calcium-Binding Proteins; Extracellular Matrix; Extracellular Matrix Proteins; Glycoproteins; Humans; Matrix Gla Protein; Minerals; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vascular Diseases

Topics: Animals; Biomarkers; Humans; Inflammation; Lipopolysaccharides; Mice; Osteoprotegerin; Respiratory Distress Syndrome; Sepsis; Vascular Diseases

The aim of this paper was to investigate the association of circulating osteoprotegerin (OPG) and receptor activator of the nuclear factor kB ligand (RANKL) levels with carotid intima-media thickness (CIMT) in type 2 diabetes mellitus (T2DM).. We performed a cross-sectional community-based study including 40 T2DM postmenopausal women and 40 healthy controls. CIMT was measured by B-mode ultrasound. Serum OPG and RANKL were measured by solid-phase enzyme-linked immunosorbent assay (ELISA).. Serum OPG levels were higher in T2DM than in controls (median 2.9 vs 2.0 pmol/liter; P<0.001), significantly associated with CIMT in T2DM (P<0.001). RANKL levels were lower in T2DM than in controls (median 0.45 vs 0.60 pmol/liter; P<0.0001), however no association was found with CIMT. Serum OPG levels were associated with cross-sectional measure of CIMT in T2DM.. The data would support the role of an increased OPG/RANKL ratio as a possible marker of progression of vascular dysfunction in diabetes.

Topics: Adult; Age Factors; Aged; Body Mass Index; Carotid Arteries; Carotid Intima-Media Thickness; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Humans; Middle Aged; Osteoprotegerin; Postmenopause; RANK Ligand; Reproducibility of Results; Sex Factors; Ultrasonography; Vascular Diseases

Twenty patients affected by chronic venous disease (CVD) in tertiary venous network and/or saphenous vein were analyzed before surgical ablation by echo-color-doppler for the hemodynamic parameters reflux time (RT) and resistance index (RI), a negative and a positive prognostic factor, respectively. RT and RI were next correlated with relevant in vitro parameters of venous endothelial cells (VEC) obtained from surgical specimens, such as cell migration in response to serum gradient, proliferation index, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 expression, as well as cytokines release. Of interest, ICAM-1 expression in patient-derived VEC cultures correlated positively with RT and negatively with RI. Moreover, RT showed a positive correlation with the baseline osteoprotegerin (OPG) expression by VEC and an inverse correlation with VEC proliferation index. On the other hand, RI correlated positively with TNF-related apoptosis inducing ligand (TRAIL) expression. Among the cytokines released by VEC, GM-CSF showed a positive correlation with VEC proliferation and TRAIL expression and a negative correlation with OPG, ICAM-1 and VCAM-1 expression. Since in vitro recombinant GM-CSF induced VEC proliferation and counteracted the induction of ICAM-1, VCAM-1 and OPG upon exposure to TNF-α, our data suggest an anti-inflammatory activity of GM-CSF on venous endothelial cells.

Topics: Aged; Anti-Inflammatory Agents; Apoptosis; Cell Membrane; Cell Movement; Cell Proliferation; Cohort Studies; Endothelial Cells; Female; Gene Expression Regulation; Granulocyte-Macrophage Colony-Stimulating Factor; Hemodynamics; Humans; Intercellular Adhesion Molecule-1; Male; Middle Aged; Osteoprotegerin; Recombinant Proteins; Time Factors; TNF-Related Apoptosis-Inducing Ligand; Ultrasonography, Doppler; Vascular Cell Adhesion Molecule-1; Vascular Diseases

Topics: alpha-2-HS-Glycoprotein; Calcinosis; Calciphylaxis; Calcium-Binding Proteins; Extracellular Matrix Proteins; Humans; Kidney Function Tests; Male; Matrix Gla Protein; Osteoprotegerin; Vascular Diseases; Young Adult

High PTH levels have been reported in patients with chronic heart failure (CHF). Similarly, its levels increase with aging and are related to impaired survival in elderly adults. However, its relationship with neuroendocrine activation and endothelial dysfunction in CHF has not been previously studied. Seventy-three CHF males with New York Heart Association (NYHA) classes II and III and 20 control subjects aged ≥ 55 yr were recruited. PTH, 25-hydroxyvitamin D [25(OH)D], N-terminal pro-brain natriuretic peptide (NT-pro-BNP), adiponectin, and osteoprotegerin were measured. Endothelial function (brachial flow mediated dilation), echocardiography, physical performance, and quality of life were assessed, as well. CHF patients had markedly increased serum PTH (77 ± 33 vs 40 ± 11 pg/ml, p<0.0001), NT-pro-BNP [1809 (2742) vs 67 (74) pg/ml, p<0.0001], adiponectin (17 ± 9 vs 10 ± 2 μg/ml, p<0.0001), osteoprotegerin, whereas 25(OH)D levels were decreased compared to controls. Increased PTH is positively correlated with NTpro- BNP (r=0.399, p<0.0001), adiponectin (r=0.398, p<0.0001), and osteoprotegerin, whereas negatively with 25(OH)D in CHF patients. Additionally, increased serum PTH was associated with endothelial dysfunction, echocardiographic variables of heart failure progression, impaired physical performance, and deteriorated quality of life. In a multivariate linear regression analysis, increased serum PTH was independently associated with neuroendocrine activation (NT-pro-BNP, adiponectin) and endothelial dysfunction in elderly CHF men (R2=0.455). Additionally, demonstrated relations with other well-established variables of heart failure severity suggest the potential role of serum PTH in the pathogenesis and non-invasive monitoring of heart failure progression. Future studies are needed to evaluate the predictive value of serum PTH for clinical outcomes as well as beneficial potential of PTH suppression in CHF patients.

Topics: Adiponectin; Aged; Chronic Disease; Endothelium, Vascular; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Neurosecretory Systems; Osteoprotegerin; Parathyroid Hormone; Peptide Fragments; ROC Curve; Vascular Diseases; Vitamin D

Osteoprotegerin (OPG) inhibits vascular calcification in vitro, and OPG(-/-) mice develop vascular calcification. Insulin-like growth factor-1 (IGF1) signalling has been implicated in vascular smooth muscle cell (VSMC) survival; however, the role of IGF1-receptor (IGF1R) expression in calcification is unclear. We sought to determine whether the protective effects of OPG in vascular calcification were mediated by IGF1R.. Calcium-induced mineralization of VSMCs was blocked in cells expressing the IGF1R and by treatment with OPG. OPG induced IGF1R mRNA, protein, and transcription optimally at 1 ng/mL. Calcium also positively regulated both OPG and IGF1R, and siRNA targeting of OPG inhibited calcium-inducible IGF1R mRNA. Addition of calcium to VSMCs reduced camptothecin-stimulated apoptosis and increased expression of survival genes Bcl2 and nuclear factor-kappa B without altering levels of proliferation. Calcium's induction of IGF1R and OPG was dose and time dependent but was blunted at higher calcium doses. Calcium- and OPG-inducible IGF1R transcription occurred between -446 and -188 bp of the IGF1R promoter, and inducible-IGF1R expression was blocked by specificity protein-1 (Sp1) silencing studies. Furthermore, elevated IGF1R and OPG protein levels were present in calcified atherosclerotic tissue.. We have shown for the first time that IGF1R expression and activity via OPG can modulate VSMC calcification in vitro. We suggest a feedback mechanism: moderate calcium levels increase OPG, which then increases IGF1R to enhance VSMC survival and block calcification induced by calcium. In contrast, high calcium leads to inhibition of IGF1R expression and activity to stimulate VSMC calcification further.

Topics: Animals; Apoptosis; Calcinosis; Calcium; Camptothecin; Cells, Cultured; Feedback, Physiological; Gene Expression Regulation; Humans; Muscle, Smooth, Vascular; Mutation; Myocytes, Smooth Muscle; NF-kappa B; Osteoprotegerin; Proto-Oncogene Proteins c-bcl-2; Rats; Receptor, IGF Type 1; RNA Interference; RNA, Messenger; Sp1 Transcription Factor; Time Factors; Transfection; Vascular Diseases

Topics: Animals; Bone Morphogenetic Protein 4; Bone Remodeling; Calcinosis; Humans; Muscle, Smooth, Vascular; Osteolysis; Osteoprotegerin; RANK Ligand; Rats; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction; Vascular Diseases

Cardiovascular disease is the leading cause of death in the chronic kidney disease (CKD) population. The mechanisms of vascular damage are not fully understood. The objective of this study was to prospectively investigate the importance of novel mediators of vascular damage, in conjunction with vascular calcification (VC), on survival.. A total of 134 subjects [60 haemodialysis (HD), 28 peritoneal dialysis (PD) and 46 CKD stage 4] were studied. All survivors completed 40 months of follow-up. VC was measured using multi-slice spiral CT of the superficial femoral artery. Circulating osteoprotegerin (OPG), Fetuin-A and high sensitivity C-reactive protein (hs-CRP) were measured in addition to standard clinical biochemical analysis.. After a 40-month follow-up, 31 patients had died (27 men and 4 women). Of 31 subjects, 31 had evidence of significant VC. The majority of deaths were in the HD group (48%), 36% were PD subjects and 16% were CKD subjects. The outcome of interest was survival at the end of follow-up. Multivariate logistical regression analysis revealed male gender [OR 8.06 (1.34-48.450) P = 0.02], OPG >25 pmol/L [OR 5.31(1.35-20.88) P = 0.02] and hypoalbuminaemia [OR 0.26 (0.12-0.56) P < 0.01], were associated with increased odds of death.. We have previously reported that VC and low albumin predict death in CKD stages 4 and 5 over a 2-year follow-up period. These data show that OPG, independent of CRP, is also associated with a negative outcome. The mechanisms remain to be elucidated; however, it is likely that they are associated with vascular damage through mechanisms in addition to VC.

Topics: C-Reactive Protein; Calcinosis; Cause of Death; Chronic Disease; Female; Humans; Kidney Diseases; Male; Middle Aged; Osteoprotegerin; Prospective Studies; Severity of Illness Index; Survival Rate; Time Factors; Vascular Diseases

Topics: Calcinosis; Humans; Osteoprotegerin; Receptor Activator of Nuclear Factor-kappa B; Vascular Diseases

The role of osteoprotegerin in vascular disease is unclear. Recent observational studies show that serum osteoprotegerin levels are associated with the severity and progression of coronary artery disease, atherosclerosis, and vascular calcification in patients. However, genetic and treatment studies in mice suggest that osteoprotegerin may protect against vascular calcification.. To test whether osteoprotegerin induces or prevents vascular disease, we treated atherogenic diet-fed ldlr(-/-) mice with recombinant osteoprotegerin (Fc-OPG) or vehicle for 5 months. Vehicle-treated mice developed significant, progressive atherosclerosis with increased plasma osteoprotegerin levels, consistent with observational studies, and approximately 15% of these atherosclerotic lesions developed calcified cartilage-like metaplasia. Treatment with Fc-OPG significantly reduced the calcified lesion area without affecting atherosclerotic lesion size or number, vascular cytokines, or plasma cholesterol levels. Treatment also significantly reduced tissue levels of aortic osteocalcin, a marker of mineralization.. These data support a role for osteoprotegerin in the vasculature as an inhibitor of calcification and a marker, rather than a mediator, of atherosclerosis.

Topics: Animals; Aorta; Atherosclerosis; Calcinosis; Endothelium, Vascular; Mice; Mice, Knockout; Osteoprotegerin; RANK Ligand; Receptors, LDL; Recombinant Proteins; RNA, Messenger; Vascular Diseases

Osteoprotegerin (OPG) has recently been implicated in human atherogenesis. Abdominal obesity represents an established risk factor for the onset and development of atherosclerotic damage. The aim of the present study was to investigate the link between OPG and abdominal fat and the relationship to precocious features of atherosclerotic disease such as brachial flow-mediated vasodilation (FMV) and the intima-media thickening (IMT) in 195 white postmenopausal women (age range, 43-75 years). The study population was divided into 2 groups: group 1-waist circumference <80 cm and group 2-waist circumference > or = 80 cm. Group 2 had higher menopausal years, body mass index, low-density lipoprotein cholesterol, triglycerides, C-reactive protein, and carotid IMT. High-density lipoprotein cholesterol was higher in group 1. Afterward, these groups were divided on the basis of a cutoff value of OPG (6.85 pmol/L) that was the median of its distribution: patients with OPG < or = 6.85 pmol/L were OPG(-), and those with OPG >6.85 pmol/L were OPG(+). The OPG(+) subjects in both had lower brachial FMV and higher carotid IMT in comparison with OPG(-) subjects. At the multivariate regression analysis, waist circumference, high-density lipoprotein cholesterol, C-reactive protein, and OPG were predictors of carotid mean IMT (beta = 0.55, P = .001; beta = -0.14, P = .001; beta = 0.16, P = .001; and beta = 0.14, P = .05, respectively) and age, OPG, low-density lipoprotein cholesterol, and brachial diameter of brachial FMV (beta = -0.13, P = .05; beta = -0.25, P = .001; beta = -0.14, P = .024; and beta = 0.48, P = .001, respectively). The conclusions are as follows: first, OPG levels did not appear to be conditioned by a risk factor such as abdominal obesity; and second, OPG levels are mainly linked to the evidence of vascular damage. On this basis, we could speculate that OPG levels may be considered not a cardiovascular risk condition but a defense against atherosclerotic progression.

Topics: Abdominal Fat; Adult; Aged; Aging; Anthropometry; Arteries; Atherosclerosis; Bone Remodeling; Brachial Artery; C-Reactive Protein; Carotid Arteries; Cholesterol, HDL; Cholesterol, LDL; Endothelium, Vascular; Female; Humans; Middle Aged; Osteoprotegerin; Postmenopause; Ultrasonography; Vascular Diseases; Vasodilation

We tested the effects of calcitriol and its analog paricalcitol on VSMC calcification in vitro and in vivo. For that reason, cells and animals with five-sixths nephrectomy were treated with both compounds. Calcitriol, but not paricalcitol, increased VSMC calcification in vitro and in vivo independently of calcium and phosphate levels. This increase in calcification was parallel to an increase in the RANKL/OPG ratio.. Vascular calcification is a common finding in patients with endstage renal disease. Furthermore, those patients often present secondary hyperparathyroidism, partly because of a decrease of calcitriol synthesis on the kidney. Thus, one of the main therapeutic options is to treat those patients with calcitriol or analogs. However, this treatment presents unwanted side effects, such as increases in vascular calcification.. We tested the effect on vascular smooth muscle cell (VSMC) calcification of calcitriol and one of its analogs, paricalcitol, in vitro and in vivo in animals with endstage renal disease.. Calcitriol increased calcification of VSMCs cultured in calcification media. This effect was not present when cells were incubated with paricalcitol. Furthermore, only cells incubated with calcitriol showed an increased RANKL/osteoprotegerin (OPG) expression. Animals with renal failure treated with hypercalcemic doses of calcitriol and paricalcitol showed an increase in systolic blood pressure. However, diastolic blood pressure only raised significantly in those animals treated with paricalcitol. This effect led to a significant increase in pulse pressure in animals treated with calcitriol. The increase in pulse pressure was likely caused by the extensive calcification observed in arteries of animals treated with calcitriol. This increase in calcification was not seen in arteries of animals treated with paricalcitol, despite having similar levels of serum calcium and phosphorus as animals treated with calcitriol. Furthermore, the decreases in serum PTH levels were similar in both treatments.. We conclude that paricalcitol has a different effect than calcitriol in VSMC calcification and that this could explain part of the differences observed in the clinical settings.

Topics: Animals; Aorta; Blood Pressure; Bone Density Conservation Agents; Calcinosis; Calcitriol; Calcium; Cells, Cultured; Ergocalciferols; Gene Expression; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nephrectomy; Osteoprotegerin; Parathyroid Hormone; Phosphorus; RANK Ligand; Rats; Rats, Sprague-Dawley; Vascular Diseases; Vitamin D

Topics: Biomarkers; Coronary Artery Disease; Humans; Osteoprotegerin; Vascular Diseases

The majority of patients with chronic kidney disease (CKD) have excessive vascular calcification; however, most studies demonstrate that a subset of CKD patients do not have, nor develop, vascular calcification despite similar exposure to the uremic environment. This suggests protective mechanisms, or naturally occurring inhibitors, of calcification may be important.. In order to determine the role of three inhibitors, fetuin-A, matrix gla protein (MGP), and osteoprotegerin (OPG) in the vascular calcification observed in patients with CKD-5, we (1) measured serum levels of these inhibitors and compared the levels to calcification assessed by computed tomography (CT); (2) examined arteries from CKD-5 patients by immunostaining for these inhibitors; and (3) examined the expression and effect of these inhibitors in cultured bovine vascular smooth muscle cells (BVSMCs) incubated in serum pooled from uremic patients compared to healthy controls.. There was a negative correlation of coronary artery calcification scores with serum fetuin-A levels (r=-0.30, P= 0.034) and a positive association with OPG levels (r= 0.29, P= 0.045). There was increasing immunostaining for both fetuin-A and MGP in arteries with increasing calcification graded semiquantitatively (P < 0.003). In vitro, fetuin-A added to mineralizing BVSMCs inhibited mineralization (P < 0.001). Compared to normal serum, BVSMCs incubated with uremic serum had a progressive increase in MGP expression with mineralization (P < 0.001) and increased expression of OPG in BVSMCs (P < 0.04).. These data demonstrate that fetuin-A, OPG, and MGP play an important role in the pathogenesis of uremic vascular calcification.

Topics: alpha-2-HS-Glycoprotein; Animals; Blood Proteins; Calcinosis; Calcium-Binding Proteins; Cattle; Cells, Cultured; Chronic Disease; Extracellular Matrix Proteins; Glycoproteins; Humans; Kidney Diseases; Matrix Gla Protein; Muscle, Smooth, Vascular; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vascular Diseases

Vascular calcification, such as coronary and aortic calcification, is a significant feature of vascular pathology. Two distinct forms of vascular calcification are well recognized. One is medial calcification, which occurs between the cell layers of smooth muscle cells, and is related to aging, diabetes and chronic renal failure. The other is atherosclerotic calcification, which occurs in the intima during the development of atheromatous disease. It has been shown that statins inhibit the progression of calcification in the aortic valve and the coronary artery. We have found that statins inhibit calcification of human aortic smooth muscle cells, which is induced by incubating the cells in high-phosphate medium. We also found that this is mediated by inhibiting cellular apoptosis, an essential mechanism for calcification, not by inhibiting inorganic phosphate (Pi) uptake by sodium-dependent phosphate cotransporter (NPC). Besides apoptosis and Pi uptake, such proteins as osteoprotegerin (OPG), matrix Gla protein (MGP), Klotho, fetuin-A, and apoE have been shown to negatively affect vascular calcification. Many previous reports suggest that vascular calcification appears to be regulated by promoting factors, such as Pi, apoptosis, modified LDL, advanced glycation end products, oxidative stress, vitaminD3, glucocorticoid, cbfa-1, osteopontin, and inhibitory factors, such as OPG, MGP, Klotho, fetuin-A, PTH/PTHrP, pyrophosphate, statins, and bisphosphonates. The precise mechanism of vascular calcification is of interest.

Topics: Animals; Apoptosis; Atherosclerosis; Calcinosis; Cell Cycle Proteins; Glucuronidase; Glycoproteins; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Klotho Proteins; Membrane Proteins; Mice; Osteoprotegerin; Peptide Elongation Factor 1; Phosphates; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vascular Diseases

Topics: Calcinosis; Carrier Proteins; Glycoproteins; Humans; Male; Membrane Glycoproteins; Middle Aged; Osteoprotegerin; Popliteal Artery; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vascular Diseases

Osteoprotegerin is a novel member of the tumor necrosis factor receptor superfamily and a soluble decoy receptor of the receptor activator of nuclear factor-kappaB ligand. Recent experimental research has implicated osteoprotegerin in atherogenesis, but epidemiological confirmation of this concept is sparse.. As part of the prospective, population-based Bruneck Study, severity, initiation, and progression of atherosclerosis were assessed in carotid arteries. Cases of incident cardiovascular disease and vascular mortality were carefully recorded over a 10-year period (1990 to 2000). Osteoprotegerin levels were measured in samples obtained at baseline and during follow-up. Serum osteoprotegerin showed a strong association with numerous vascular risk factors, including age, diabetes, markers of systemic inflammation, chronic infection, and smoking. In multivariate analyses, osteoprotegerin was significantly related to severity and 10-year progression of carotid atherosclerosis. Furthermore, a high level of osteoprotegerin was an independent risk factor for incident cardiovascular disease (adjusted relative risk for the top versus bottom tertile group for osteoprotegerin 2.2 [1.3 to 3.8]; P=0.001) and vascular mortality (adjusted relative risk for the top versus bottom tertile group for osteoprotegerin 3.1 [1.2 to 8.2]; P=0.010) but not for mortality due to nonvascular causes.. Osteoprotegerin is an independent risk factor for the progression of atherosclerosis and onset of cardiovascular disease.

Topics: Aged; Aged, 80 and over; Apoptosis; Biomarkers; Calcinosis; Cardiovascular Diseases; Carotid Artery Diseases; Cohort Studies; Comorbidity; Disease Progression; Female; Follow-Up Studies; Glycoproteins; Humans; Incidence; Italy; Male; Middle Aged; Odds Ratio; Osteoprotegerin; Prospective Studies; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk; Risk Factors; Sampling Studies; Ultrasonography; Vascular Diseases

Vascular calcification may occur at different areas of the vessel wall, including the intima in atherosclerosis and the media in Mönckeberg's sclerosis. Medial calcification of arteries is common in patients with diabetes mellitus or chronic renal failure. Osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand are essential modulators of bone homeostasis and may be involved in the process of vascular calcification. In this study we investigated arteries from patients with Mönckeberg's sclerosis and atherosclerosis. Apoptosis, which precedes vascular calcification in vitro, was assessed by an in situ ligation assay and was localized to the medial layer of arteries (Mönckeberg's sclerosis) and the neointima (atherosclerosis). Immunohistochemistry and in situ hybridization revealed OPG immunoreactivity and mRNA expression surrounding calcified areas in the medial layer (Mönckeberg's sclerosis), whereas OPG was mainly expressed adjacent to calcified neointimal lesions (atherosclerosis). Receptor activator of nuclear factor-kappaB ligand protein and mRNA were barely or not detectable. Of note, TNF-related apoptosis-inducing ligand, an inducer of apoptosis that is also blocked by OPG, displayed a similar spatial distribution as OPG. In summary, we demonstrate enhanced apoptosis adjacent to vascular calcification, and the concurrent expression of regulators of apoptosis and osteoclastic differentiation, TNF-related apoptosis-inducing ligand and OPG, suggesting their involvement in the pathogenesis of vascular calcification.

Topics: Aged; Aged, 80 and over; Apoptosis Regulatory Proteins; Arteriosclerosis; Calcinosis; Carrier Proteins; Case-Control Studies; Female; Glycoproteins; Humans; Immunohistochemistry; In Situ Hybridization; Male; Membrane Glycoproteins; Middle Aged; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; RNA, Messenger; Staining and Labeling; Tissue Distribution; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha; Vascular Diseases

Topics: Glycoproteins; Humans; Osteoporosis; Osteoprotegerin; Polymorphism, Genetic; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk Factors; Vascular Diseases

Topics: Animals; Bone Remodeling; Calcinosis; Female; Glycoproteins; Humans; Mice; Osteoporosis; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vascular Diseases

The present experiments were carried out to test the hypothesis that arterial calcification is linked to bone resorption by determining whether the selective inhibition of bone resorption with osteoprotegerin will inhibit arterial calcification. In the first test, arterial calcification was induced by treating 22-day-old male rats with warfarin, a procedure that inhibits the gamma-carboxylation of matrix Gla protein and causes extensive calcification of the arterial media. Compared with rats treated for 1 week with warfarin alone, rats treated with warfarin plus osteoprotegerin at a dose of 1 mg/kg per day had dramatically reduced alizarin red staining for calcification in the aorta and in the carotid, hepatic, mesenteric, renal, and femoral arteries, and they had 90% lower levels of calcium and phosphate in the abdominal aorta (P<0.001) and in tracheal ring cartilage (P<0.01). More rapid arterial calcification was induced by treating 49-day-old male rats with toxic doses of vitamin D. Treatment for 96 hours with vitamin D caused widespread alizarin red staining for calcification in the aorta and the femoral, mesenteric, hepatic, renal, and carotid arteries, and osteoprotegerin completely prevented calcification in each of these arteries and reduced the levels of calcium and phosphate in the abdominal aorta to control levels (P<0.001). Treatment with vitamin D also caused extensive calcification in the lungs, trachea, kidneys, stomach, and small intestine, and treatment with osteoprotegerin reduced or prevented calcification in each of these sites. Measurement of serum levels of cross-linked N-teleopeptides showed that osteoprotegerin dramatically reduced bone resorption activity in each of these experiments (P<0.001). Therefore, we conclude that doses of osteoprotegerin that inhibit bone resorption are able to potently inhibit the calcification of arteries that is induced by warfarin treatment and by vitamin D treatment. These results support the hypothesis that arterial calcification is linked to bone resorption.

Topics: Animals; Arteries; Bone Resorption; Calcinosis; Collagen; Collagen Type I; Drug Antagonism; Glycoproteins; Lung; Male; Osteoprotegerin; Peptides; Rats; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Trachea; Vascular Diseases; Vitamin D; Warfarin

Osteoprotegerin (OPG) is a secreted protein that inhibits osteoclast formation. In this study the physiological role of OPG is investigated by generating OPG-deficient mice. Adolescent and adult OPG-/- mice exhibit a decrease in total bone density characterized by severe trabecular and cortical bone porosity, marked thinning of the parietal bones of the skull, and a high incidence of fractures. These findings demonstrate that OPG is a critical regulator of postnatal bone mass. Unexpectedly, OPG-deficient mice also exhibit medial calcification of the aorta and renal arteries, suggesting that regulation of OPG, its signaling pathway, or its ligand(s) may play a role in the long observed association between osteoporosis and vascular calcification.

Topics: Animals; Arteries; Bone Density; Calcinosis; Disease Models, Animal; Female; Gene Targeting; Glycoproteins; In Situ Hybridization; Male; Mice; Mice, Knockout; Osteoporosis; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vascular Diseases

Calcification of extracellular matrix (ECM) can be either physiological or pathological. Physiological calcification (or mineralization) of ECM is restricted to bones, teeth and, to a lesser extent, growth plate cartilages. Pathological calcification appears often in the ECM of arteries where it is a frequent complication of atherosclerosis. However, calcification of the ECM of arteries is not restricted to atherosclerosis. Indeed, human diseases have been described that are characterized by calcification of the aortic media in the absence of any atherosclerotic lesions. The existence of these rare diseases, along with several mouse models recently generated and discussed below, indicates that the formation of atherosclerotic lesions and the calcification of the artery ECM are controlled by different genetic pathways. This emerging knowledge has implications for our understanding of ECM calcification beyond atherosclerosis.

Topics: Animals; Arteries; Arteriosclerosis; Calcinosis; Calcium-Binding Proteins; Extracellular Matrix; Extracellular Matrix Proteins; Glycoproteins; Humans; Matrix Gla Protein; Mice; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vascular Diseases; Vitamin K