Subject(s)
Calciphylaxis/physiopathology , Vascular Diseases/physiopathology , Calcinosis/etiology , Calcinosis/pathology , Calcinosis/physiopathology , Calciphylaxis/etiology , Calciphylaxis/pathology , Calcium-Binding Proteins/blood , Calcium-Binding Proteins/metabolism , Extracellular Matrix Proteins/blood , Extracellular Matrix Proteins/metabolism , Humans , Kidney Function Tests , Male , Osteoprotegerin/blood , Osteoprotegerin/metabolism , Vascular Diseases/etiology , Vascular Diseases/pathology , Young Adult , alpha-2-HS-Glycoprotein/metabolism , Matrix Gla ProteinABSTRACT
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. We identified OSCAR on the surface of human primary endothelial cells. Stimulation of endothelial cells with oxidized low-density lipoprotein (oxLDL) caused a time- and dose-dependent induction of OSCAR, which was lectin-like oxidized LDL receptor 1 and Ca(2+) dependent. OSCAR was transcriptionally regulated by oxLDL as shown by OSCAR promoter analysis. Specific inhibition of the nuclear factor of activated T cells (NFAT) pathway prevented the oxLDL-mediated increase of endothelial OSCAR expression. As assessed by EMSA, oxLDL induced binding of NFATc1 to the OSCAR promoter. Notably, in vivo-modified LDL from patients with diabetes mellitus stimulated OSCAR mRNA expression in human endothelial cells. Furthermore, apolipoprotein E knockout mice fed a high-fat diet showed an enhanced aortic OSCAR expression associated with increased expression of NFATc1. In summary, OSCAR is expressed in vascular endothelial cells and is regulated by oxLDL involving NFATc1. Our data suggest that OSCAR, originally described in bone as immunological mediator and regulator of osteoclast differentiation, may be involved in cell activation and inflammation during atherosclerosis.
Subject(s)
Endothelial Cells/metabolism , Lipoproteins, LDL/physiology , Receptors, Cell Surface/genetics , Animals , Atherosclerosis/pathology , Cells, Cultured , Endothelium, Vascular/cytology , Gene Expression Regulation , Humans , Inflammation/etiology , Mice , Mice, Knockout , NFATC Transcription Factors , Promoter Regions, Genetic , Receptors, Cell Surface/biosynthesis , Transcriptional ActivationABSTRACT
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. OSCAR expression in bone is highly conserved across different species, and the molecule is an important costimulatory receptor for osteoclast differentiation through activation of NFATc1. In humans, OSCAR is expressed by macrophages, monocytes, and monocyte-derived dendritic cells and modulates the response of the innate and adaptive immune systems by promoting cell activation and maturation, Ag presentation, and proinflammatory circuits. Human studies indicate that OSCAR may contribute to the pathogenesis and severity of osteoporosis and rheumatoid arthritis. In this paper, we review the structure-function relationship, expression pattern, and physiological role of OSCAR in osteoimmunology and summarize its potential implications for human diseases.