No abstract

Osteoprotegerin (OPG) regulates osteoclast and immune functions and appears to represent a protective factor for the vascular system. However, the role of OPG in human atherosclerosis has not been evaluated. In this study, we assessed OPG serum levels in 522 age-matched men who, on the basis of coronary angiography, had either absence of coronary artery disease (CAD) or presence of single-vessel disease, double-vessel disease, or severe triple-vessel disease. OPG serum levels were positively correlated with age (r = 0.28; P < 0.001) and were higher in men with diabetes mellitus (P < 0.01). OPG serum levels in men without CAD were 5.4 +/- 2.0 pmol/liter, compared with 6.1 +/- 2.1 pmol/liter in single-vessel disease (P < 0.005), 5.9 +/- 2.4 in double-vessel disease (P < 0.05), and 6.3 +/- 2.3 pmol/liter in triple-vessel disease (P < 0.001). Moreover, OPG serum levels were positively correlated with the severity of CAD as determined by a CAD scoring system (r = 0.17; P < 0.01). In conclusion, our data underline that OPG serum levels are associated with the severity of CAD and are increased in elderly men and patients with diabetes mellitus. We conclude that increased OPG serum levels may reflect advanced cardiovascular disease in men.

Patients with osteoporosis frequently suffer from vascular calcification, which was shown to predict both cardiovascular morbidity/mortality and osteoporotic fractures. Various common risk factors and mechanisms have been suggested to cause both bone loss and vascular calcification, including aging, estrogen deficiency, vitamin D and K abnormalities, chronic inflammation and oxidative stress. Major breakthroughs in molecular and cellular biology of bone metabolism and the characterization of knockout animals with deletion of bone-related genes have led to the concept that common signaling pathways, transcription factors and extracellular matrix interactions may account for both skeletal and vascular abnormalities. For example, mice that lack the cytokine decoy receptor osteoprotegerin or the hormone Klotho display a combined osteoporosis-arterial calcification phenotype. In this review, we summarize the current data and evaluate potential mechanisms of the osteoporosis-arterial calcification syndrome. We propose a unifying hypothesis of vascular calcification that combines both active and passive mechanisms of vascular mineralization with aspects of bone resorption and age-related changes.

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.

The human uterus is generally considered to be an immunologically privileged site that isolates the implanted allogeneic embryo from an aggressive maternal immune response. This is in contrast to the fact that the decidua, like other mucosal surfaces, must be able to respond to different types of foreign antigens, including pathogenic organisms, seminal plasma, and fetal trophoblasts (FTBs). However, during hemochorial placentation, the direct contact between FTBs (which invade uterine mucosa, the decidua) and maternal immunocompetent cells in the decidua 1 suggests that mechanisms of tolerance must exist to avoid rejection of the conceptus.The human decidua is invested with a significant (up to 75% of all major histocompatibility complex (MHC) class I ϩ cells are CD45 ϩ ) and diverse population of leukocytes. 2,3 Nearly one fifth of decidual leukocytes are positive for MHC class II and are thought to be mostly macrophages. 4 The most abundant cell type of decidua are uterine-specific natural killer cells, the large granular lymphocytes (LGLs), 5 whereas T cells are sparse and B cells are virtually absent. 3,5 The decidual leukocyte population has been a center of interest for the understanding of the balance between maternal control of the extent of invasion of FTBs in the uterine wall 2-6 as well as acceptance of the allogeneic fetus in successful pregnancy.

Vascular calcification is associated with increased cardiovascular morbidity and mortality. A number of calcification inhibitors have been defined recently, including inorganic pyrophosphate (PP(i)), an important physicochemical inhibitor of hydroxyapatite crystal growth. Increased hydrolysis of PP(i) by tissue-nonspecific alkaline phosphatase (TNAP) may occur in renal failure and act to enhance mineralization of vessels.

Abstract-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-B 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-B, 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. 4 or follicular dendritic cell-derived receptor-1 (FDCR-1) 5 have been coined. According to the American Society for Bone and Mineral Research Committee, the term osteoprotegerin (OPG) is now being recommended. 6 The mouse 7 and the human 8 OPG genes have been cloned and characterized, and the human OPG gene represents a single-copy gene that contains 5 exons and spans 29 kb of the human genome located on chromosome 8. 9 Murine OPG gene expression starts between days 8 and 9 during embryogenesis. 7 Of note, the human OPG promoter sequence harbors binding elements for the osteoblast-specific transcription factor cbfa-1, which was found to increase OPG gene transcription. 10 OPG is a member of the tumor necrosis factor receptor (TNFR) superfamily, and it represents a secretory basic glycoprotein that exists in a 60-kd monomeric form and a disulfide-linked homodimeric form of 120 kd. 11 It has also been detected in a cell surface-associated form with some cell types, 5 although sequence analysis failed to detect a classical hydrophobic transmembrane domain, which is typical for all other members of the TNFR superfamily. 11 The molecule is composed of 401 amino acid residues as deduced from cDNA nucleotide sequencing with a signal peptide of 21 amino acids. 3 OPG consists of 7 structural domains, of which the amino-terminal cysteine-rich domains 1 to 4 share some features with the extracellular domains of other members of the TNFR family (Figure 1). 12 Mutation analyses have been used for functional characterization of OPG. Domains 1 to 4 are sufficient for conferring osteoclastogenesis inhibitory activity, which can be demonstrated by...

Chronic kidney disease (CKD) is associated with fatal cardiovascular consequences in part due to ectopic calcification of soft tissues particularly arteries, capillaries, and cardiac valves. An increasing body of evidence from experimental studies and in vivo data suggest that (I) a mineral imbalance with hyperphosphatemia and high-circulating calcium x phosphate product, (II) a deficiency of systemic or local calcification inhibitors, (III) death or 'damage' of vascular smooth muscle cells (VSMCs), and/or (IV) phenotypic transformation of VSMCs to osteo/chondrocytic cells may all act in concert to initiate and sustain vascular calcification. In CKD patients inhibitory systems are overwhelmed by a multitude of agents that induce VSMC damage and cell death resulting in the release of vesicles capable of nucleating basic calcium phosphate. Studies with genetically altered mice have identified both local and systemic calcification inhibitors that act to maintain VSMC differentiation or regulate vesicle properties. However, for many of these proteins the mechanisms and sites of action are still under investigation. In particular, it is unclear whether factors present in the circulation have an inhibitory role there and whether circulating levels of these proteins influence or are indicative of underlying disease processes in individual patients. A greater understanding of the origins and roles of potential circulating inhibitors may result in novel strategies aimed at the prevention or reversal of the life-limiting calcifying vasculopathies seen in CKD patients.