The Role of the Osteoprotegerin/RANKL/RANK System in Diabetic Vascular Disease

Abstract

Over the last years our knowledge on the mechanisms involved in the pathogenesis of cardiovascular disease has been enriched by the discovery of new molecules emerging as novel risk factors. Osteoprotegerin (OPG) is a soluble glycoprotein, member of the tumor necrosis factor (TNF)-related superfamily, involved in bone resorption. It was first described as a key regulator of bone homeostasis and vascular calcification in mice. Clinical studies have suggested that serum OPG is associated with vascular calcification in humans. The role of OPG in the development of macroangiopathy in diabetes is not yet clear. It is possible that the increased OPG levels in diabetes reflect a compensatory response to arterial injury and that it is not involved in the pathogenesis of atherosclerosis. Whether harmful or not, determination of serum OPG levels has been suggested as a prognostic biomarker of cardiovascular disease. In addition, increased OPG levels have been reported in diabetic patients with microvascular complications. The potential of OPG administration for therapeutic reasons is challenging for future investigators. This review summarizes the current knowledge on the association between OPG and macrovascular as well microvascular complications of diabetes.

Anti-Osteoporotic Drugs and Vascular Calcification: The Bidirectional Calcium Traffic

“…Numerous clinical studies have reported a consistent association between serum OPG levels and cardiovascular events and mortality, which suggests a role for OPG as a marker rather than a mediator of atherosclerosis and confirms previous in vivo studies [106,107,108,109,110]. …”

The Alliance of Mesenchymal Stem Cells, Bone, and Diabetes

“…Indeed, levels of OPG are associated with fat mass [47] and atherosclerosis parameters in diabetes [47–49], while soluble RANKL have been shown to predict T2D in humans and to participate in the genesis of insulin resistance in this disease (see Section 5.6) [50]. …”

“…Both liver tissues [243] and β -cells express RANKL and RANK [50]. Moreover, levels of OPG, which competes for RANK/RANKL interaction, are elevated in T2D, especially in those with poor glycemic control, and relates with fat mass and atherosclerosis parameters [47–49, 244]. Recently, Kiechl et al showed that increased levels of soluble RANKL are associated with the development of diabetes in 844 subjects from the Brunek study (OR = 3.37; 95%CI: 1.63–6.97).…”

The Effects of Initial Periodontal Therapy on the Serum Receptor Activator of Nuclear Factor‐κβ Ligand/Osteoprotegerin System in Patients With Type 2 Diabetes Mellitus and Periodontitis

“…However, recent studies have indicated that the RANKL/OPG system might also be involved in the process of vascular calcification and insulin resistance and may be linked to cardiovascular disease and T2DM 15 , 16 . Some articles reported that serum levels of OPG in individuals with T2DM are increased compared with healthy controls, and RANKL levels are significantly reduced 17–19 .…”