Prothrombin Loading of Vascular Smooth Muscle Cell-Derived Exosomes Regulates Coagulation and Calcification.

Objective: The drug warfarin blocks carboxylation of vitamin K-dependent proteins and acts as an anticoagulant and an accelerant of vascular calcification. The calcification inhibitor MGP (matrix Gla [carboxyglutamic acid] protein), produced by vascular smooth muscle cells (VSMCs), is a key target of warfarin action in promoting calcification; however, it remains unclear whether proteins in the coagulation cascade also play a role in calcification.

Approach And Results: Vascular calcification is initiated by exosomes, and proteomic analysis revealed that VSMC exosomes are loaded with Gla-containing coagulation factors: IX and X, PT (prothrombin), and proteins C and S.

Serum fetuin-A levels and abdominal aortic calcification in healthy men - The STRAMBO study.

Vascular calcification results from an imbalance between increased extracellular levels of calcium and phosphate, reduced solubility, and low levels of calcification inhibitors in blood or the vascular wall. Fetuin-A is a major circulating calcification inhibitor. Rodent models of fetuin-A deficit indicate its calcification inhibiting potential.

TRAIL-deficiency accelerates vascular calcification in atherosclerosis via modulation of RANKL.

The osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) cytokine system, not only controls bone homeostasis, but has been implicated in regulating vascular calcification. TNF-related apoptosis-inducing ligand (TRAIL) is a second ligand for OPG, and although its effect in vascular calcification in vitro is controversial, its role in vivo is not yet established. This study aimed to investigate the role of TRAIL in vascular calcification in vitro using vascular smooth muscle cells (VSMCs) isolated from TRAIL(-/-) and wild-type mice, as well as in vivo, in advanced atherosclerotic lesions of TRAIL(-/-)ApoE(-/-) mice.

Monocytic expression of osteoclast-associated receptor (OSCAR) is induced in atherosclerotic mice and regulated by oxidized low-density lipoprotein in vitro.

The osteoclast-associated receptor (OSCAR), primarily described as a co-stimulatory regulator of osteoclast differentiation, represents a potential link between bone metabolism and vascular biology. Previously, we identified OSCAR as an endothelial cell-derived target of the proatherogenic factor oxidized low density lipoprotein (oxLDL). Since monocytes play an important role in the progression of atherosclerosis, we assessed whether atherogenic stimuli also regulate the expression of OSCAR on monocytes.

Correlates of bone microarchitectural parameters and serum sclerostin levels in men: the STRAMBO study.

Sclerostin is predominantly expressed by osteocytes. Serum sclerostin levels are positively correlated with areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry (DXA) and bone microarchitecture assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) in small studies. We assessed the relation of serum sclerostin levels with aBMD and microarchitectural parameters based on HR-pQCT in 1134 men aged 20 to 87 years using multivariable models adjusted for confounders (age, body size, lifestyle, comorbidities, hormones regulating bone metabolism, muscle mass and strength).

Endocrine and clinical correlates of myostatin serum concentration in men--the STRAMBO study.

Context: Myostatin is expressed mainly in skeletal muscle cells and acts as an inhibitor of muscle growth and differentiation. However, data on the determinants of serum myostatin concentrations in humans are limited.

Objective: The aim of the study was to assess the correlates of serum myostatin concentrations in men.

Lipids in biocalcification: contrasts and similarities between intimal and medial vascular calcification and bone by NMR.

Pathomechanisms underlying vascular calcification biogenesis are still incompletely understood. Biomineral from human atherosclerotic intimal plaques; human, equine, and bovine medial vascular calcifications; and human and equine bone was released from collagenous organic matrix by sodium hydroxide/sodium hypochlorite digestion. Solid-state (13)C NMR of intimal plaque mineral shows signals from cholesterol/cholesteryl esters and fatty acids.

Osteoprotegerin (OPG) and TNF-related apoptosis-inducing ligand (TRAIL) levels in malignant and benign pericardial effusions.

Objectives: Osteoprotegerin (OPG) is a regulator of bone and vascular homeostasis and acts as a decoy receptor for proapoptotic TNF-related apoptosis-inducing ligand (TRAIL).

Design And Methods: We assessed pericardial and serum levels of OPG and TRAIL in pericardial effusions (PE) of malignant (mPE, n=24) or non-malignant (nPE, n=34) origin, and in pericardial fluid (PF, n=25) of coronary artery disease (CAD) patients by ELISA.

Results: OPG was at least 5 fold higher in PE or PF compared to serum, with a significantly higher ratio of pericardial to serum OPG in patients with mPE or nPE compared to PF (mPE vs.

The osteoclast-associated receptor (OSCAR) is a novel receptor regulated by oxidized low-density lipoprotein in human endothelial cells.

Cross talks between the vascular and immune system play a critical role in vascular diseases, in particular in atherosclerosis. The osteoclast-associated receptor (OSCAR) is a regulator of osteoclast differentiation and dendritic cell maturation. Whether OSCAR plays a role in vascular biology and has an impact on atherogenic processes provoked by proinflammatory stimuli is yet unknown.

Calcium and osteoprotegerin regulate IGF1R expression to inhibit vascular calcification.

Aims: 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.

Crystallizing nanoparticles derived from vascular smooth muscle cells contain the calcification inhibitor osteoprotegerin.

Osteoprotegerin (OPG), a member of the TNF receptor superfamily, was initially found to modulate bone mass by blocking osteoclast maturation and function. Rodent models have also revealed a role for OPG as an inhibitor of vascular calcification. However, the precise mode of how OPG blocks mineralization is unclear.

The role of osteoclast-associated receptor in osteoimmunology.

The term osteoimmunology is coined for molecular and cellular cross talk between the skeletal and immune system. Immunomodulatory signals have long been implicated as key regulators of bone metabolism. Recently, osteoclast-associated receptor (OSCAR), an IgG-like receptor, has been identified as an important osteoimmunological mediator.

Inhibition of receptor activator of NF-kappaB ligand by denosumab attenuates vascular calcium deposition in mice.

Osteoporosis and vascular calcification frequently coincide. A potential mediator of bone metabolism and vascular homeostasis is the triad cytokine system, which consists of receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL), its receptor RANK, and the decoy receptor osteoprotegerin. Unopposed RANKL activity in osteoprotegerin-deficient mice resulted in osteoporosis and vascular calcification.

Zoledronic acid induces apoptosis and changes the TRAIL/OPG ratio in breast cancer cells.

Breast cancer has a propensity to metastasize to bone, thus causing pathological fractures. Bisphosphonates are established drugs in the treatment of bone metastasis that inhibit osteoclast activity and interrupt the vicious cycle of osteoclast-tumor cell interactions. We evaluated the direct effects of zoledronic acid on estrogen receptor (ER)-negative MDA-MB-231 and ER-positive MCF-7 breast cancer cells.

Osteoprotegerin production by breast cancer cells is suppressed by dexamethasone and confers resistance against TRAIL-induced apoptosis.

Osteoprotegerin (OPG) is a decoy receptor for receptor activator of NF-kappaB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). While RANKL is essential for osteoclastogenesis and facilitates breast cancer migration into bone, TRAIL promotes breast cancer apoptosis. We analyzed the expression of OPG and TRAIL and its modulation in estrogen receptor-positive MCF-7 cells and receptor-negative MDA-MB-231 cells.

Prevention of glucocorticoid-induced bone loss in mice by inhibition of RANKL.

Objective: RANKL has been implicated in the pathogenesis of glucocorticoid-induced osteoporosis. This study was undertaken to evaluate the efficacy of denosumab, a neutralizing monoclonal antibody against human RANKL (hRANKL), in a murine model of glucocorticoid-induced osteoporosis.

Methods: Eight-month-old male homozygous hRANKL-knockin mice expressing a chimeric RANKL protein with a humanized exon 5 received 2.

Mineral surface in calcified plaque is like that of bone: further evidence for regulated mineralization.

Objective: Cell biological studies demonstrate remarkable similarities between mineralization processes in bone and vasculature, but knowledge of the components acting to initiate mineralization in atherosclerosis is limited. The molecular level microenvironment at the organic-inorganic interface holds a record of the mechanisms controlling mineral nucleation. This study was undertaken to compare the poorly understood interface in mineralized plaque with that of bone, which is considerably better characterized.

The circulating calcification inhibitors, fetuin-A and osteoprotegerin, but not matrix Gla protein, are associated with vascular stiffness and calcification in children on dialysis.

Background: Vascular calcification occurs in the majority of patients with chronic kidney disease, but a subset of patients does not develop calcification despite exposure to a similar uraemic environment. Physiological inhibitors of calcification, fetuin-A, osteoprotegerin (OPG) and undercarboxylated-matrix Gla protein (uc-MGP) may play a role in preventing the development and progression of ectopic calcification, but there are scarce and conflicting data from clinical studies.

Methods: We measured fetuin-A, OPG and uc-MGP in 61 children on dialysis and studied their associations with clinical, biochemical and vascular measures.

17beta-Estradiol inhibits osteoprotegerin production by the estrogen receptor-alpha-positive human breast cancer cell line MCF-7.

Estrogen regulates various cytokines and growth factors in estrogen receptor (ER)-positive human breast cancer. Receptor activator of NF-kappaB ligand (RANKL) is an essential cytokine for osteoclasts, whereas osteoprotegerin (OPG) is a soluble inhibitor for RANKL. We analyzed the regulation of the RANKL/OPG system by estrogens and androgens in the ER-positive breast cancer cell line MCF-7 and the ER-negative breast cancer cell line MDA-MB-231.

Interleukin-4 and interleukin-13 stimulate the osteoclast inhibitor osteoprotegerin by human endothelial cells through the STAT6 pathway.

Introduction: Endothelial cells of the bone vasculature modulate development, remodeling, and repair of bone by secreting osteotropic cytokines and hormones, which can act on osteoblastic and osteoclastic lineage cells. RANKL is the essential factor for differentiation, activation, and survival of osteoclasts, whereas osteoprotegerin (OPG) is a soluble decoy receptor and inhibitor for RANKL.

Materials And Methods: In this study, we analyzed the regulation of OPG by T helper 2 (Th2) cytokines interleukin (IL)-4 and the closely related IL-13 in human umbilical vein endothelial cells (HUVECs), the underlying signaling pathway, and its functional relevance on osteoclastic resorption.

TRAIL stimulates proliferation of vascular smooth muscle cells via activation of NF-kappaB and induction of insulin-like growth factor-1 receptor.

TRAIL/Apo2L (tumor necrosis factor-related apoptosis-inducing ligand) is a multifunctional protein regulating homeostasis of the immune system, infection, autoimmune diseases, and apoptosis. However, its function in normal, nontransformed tissues is not clear. Here we show that TRAIL increases vascular smooth muscle cell (VSMC) proliferation in vitro, effects that can be blocked with neutralizing antibodies to TRAIL receptors DR4 and DcR1.