Osteoprotegerin and RANKL-RANK-OPG-TRAIL signalling axis in heart failure and other cardiovascular diseases

Abstract

Osteoprotegerin (OPG) is a glycoprotein involved in the regulation of bone remodelling. OPG regulates osteoclast activity by blocking the interaction between the receptor activator of nuclear factor kappa B (RANK) and its ligand (RANKL). More and more studies confirm the relationship between OPG and cardiovascular diseases. Numerous studies have confirmed that a high plasma concentration of OPG and a low concentration of tumour necrosis factor-related apoptosis inducing ligand (TRAIL) together with a high OPG/TRAIL ratio are predictors of poor prognosis in patients with myocardial infarction. A high plasma OPG concentration and a high ratio of OPG/TRAIL in the acute myocardial infarction are a prognostic indicator of adverse left ventricular remodelling and of the development of heart failure. Ever more data indicates the participation of OPG in the regulation of the function of vascular endothelial cells and the initiation of the atherosclerotic process in the arteries. Additionally, it has been shown that TRAIL has a protective effect on blood vessels and exerts an anti-atherosclerotic effect. The mechanisms of action of both OPG and TRAIL within the cells of the vascular wall are complex and remain largely unclear. However, these mechanisms of action as well as their interaction in the local vascular environment are of great interest to researchers. This article presents the current state of knowledge on the mechanisms of action of OPG and TRAIL in the circulatory system and their role in cardiovascular diseases. Understanding these mechanisms may allow their use as a therapeutic target in cardiovascular diseases in the future.

Keywords: Endothelial cells; Heart failure; Myocardial infarction; Osteoprotegerin; RANK; TRAIL.

Fig. 1

The impact of TRAIL and OPG on the migrating ability of MSCs. (A) In vitro studies. TRAIL strongly increases the migratory activity of MSCs. The addition of OPG results in inhibition at an OPG/TRAIL ratio of 3:1, and in the case of a higher concentration of OPG (OPG/TRAIL 6:1) in the abolition of the stimulating effect of TRAIL on the migrating ability of MSCs. The addition of anti-OPG antibodies to this system restores the stimulating effect of TRAIL on the migrating ability of MSCs. (B) In vivo studies. It was found in clinical studies that patients who develop HF after MI have significantly higher OPG concentrations and a higher OPG/TRAIL ratio compared to patients who do not develop HF after MI. Clinical trials confirm that patients with MI and a higher OPG/TRAIL ratio (6:1) are more likely to develop post-infarction left ventricular remodelling, develop HF more frequently and have a higher mortality compared to those with MI and a lower OPG/TRAIL ratio (3:1). Moreover, in this group of patients with MI and a high OPG/TRAIL ratio (6:1), a lower mobilisation of MSC from bone marrow and a lower number of circulating MSCs in the peripheral blood were confirmed compared to patients with MI with a lower OPG/TRAIL ratio (3: 1). Explanation of abbreviations in the main text

Fig. 2

Mechanisms of action of OPG and TRAIL in endothelial cells. OPG exerts its biological effect on the endothelial cells in three ways. Firstly, it binds through a specific domain to its ligand RANKL, preventing it from binding to its receptor, RANK. Secondly, OPG acts directly on ECs via a heparin-binding domain that has the ability to bind to heparan sulphate proteoglycans present on the surface of cells, triggering cell-surface signalling. Thirdly, it attaches to its other ligand, TRAIL, preventing TRAIL from binding to its receptors, thereby weakening or abolishing its effects. The binding of RANK to its ligand RANKL results in the activation of a signalling cascade activating NF-kB and AP-1. Acting at the level of the cell nucleus, these molecules increase the expression of OPG and ICAM-1 and VCAM-1. OPG also activates NF-kB in ECs inducing the expression of ICAM-1 and VCAM-1 at the level of the cell nucleus, which leads to increased adhesion of leucocytes to the endothelial surface in the early stages of endothelial dysfunction. OPG greatly enhances the adherence of leucocytes to the surface of ECs through its heparin-binding domain. An important connection also exists between OPG and RAS. Activation of the AT1 receptors for Ang II causes, inter alia, an increase in the expression of VEGFS. VEGF-A and VEGF-B increase inflammation and remodelling in blood vessels by activating pro-inflammatory mechanisms and pathological angiogenesis, which are strengthened by OPG. Mutual stimulating interactions between OPG and RAS have also been confirmed. In ECs Ang II increases OPG expression and OPG increases the expression of the AT1 receptor for Ang II. TRAIL significantly increases the activity of eNOS and increases NO production in ECs. The augmented phosphorylation of eNOS and the increase in NO production in ECs under the influence of TRAIL occur through the activation of the PI3 kinase/Akt pathway. Additionally, TRAIL induces PGE2 production in ECs, mainly by increasing COX-1 activity. This effect of TRAIL is accomplished by increasing NO release. NO inhibits the activity of NF-kB and decreases the expression of ICAM-1, VCAM-1 and E-selectin in ECs and prevents increased adherence of leucocytes to the endothelial surface. Explanation of abbreviations in the main text