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. 2019 Feb 6;20(3):705. doi: 10.3390/ijms20030705

Figure 1.

Figure 1

Critical role of the nuclear factor kappa-B/nuclear factor kappa-B ligand/osteoprotegerin (RANK/RANKL/OPG) axis in the pathogenesis of inflammatory processes and vascular calcification. OPG is produced by different cells—activated cells (immune system), osteoblasts in bone. The inflammatory cells and immune cells up-regulate expression of receptor activator of the RANKL. A soluble form of RANKL, sRANKL, also circulates in the blood. The interaction between RANK and RANKL initiates a signaling and gene expression cascade, activating the transcription factor NF-κB. OPG binds to RANKL and prevents the RANKL/RANK interaction. Tumor necrosis factor (TNF) receptor-associated factors (TRAFs 2,5,6) to specific sites are present in the cytoplasmic domain of RANK. Subendothelial retention of low-density lipoprotein (LDL) and its oxidative modification (OxLDL) represent the initial event in atherogenesis. Reactive oxygen species (ROS) generated by monocytes contribute to the level of oxidation of LDL. OxLDLs induce endothelial cell (EC) expression of adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1). Nitric oxide (NO) generated in the endothelium by the catalytic action of the enzyme nitric oxide synthase (eNOS) reduces the endothelial expression of ICAM-1 and VCAM-1. In the nucleus of ECs, via NF-κB and AP -1, OPG induces the expression of ICAM-1 and VCAM-1 and promotes leukocyte adhesion, an early step in ECs dysfunction. Various pathways and mediators are involved in vascular calcification depending on the etiology of the atherosclerosis. Vascular calcification is an active cell-regulated process of mineralization implicating matrix mineral metabolism. Sensors and effectors associated with shear stress regulate cellular functions and gene expression via the activation of NF-κB target genes. Osteogenic differentiation of vascular smooth muscle cells (VSMC) plays a pivotal role in the progression of vascular calcification. RANK-RANKL-OPG and other regulatory proteins are major pathways in the progression of vascular calcification. Fibroblast growth factor21 (FGF21) and Ecto-5’-nucleotidase (CD73) contribute to the regulation of this calcification. FGF21 protects the vascular system by limiting VSMC calcification. CD73 hydrolyses extracellular AMP to adenosine. Adenosine has been shown to play a protective role against calcification.