RANKL–OPG and RAGE modulation in vascular calcification and diabetes: novel targets for therapy

Abstract

Type 2 diabetes is associated with increased cardiovascular morbidity and mortality and early vascular ageing. This takes the form of atherosclerosis, with progressive vascular calcification being a major complication in the pathogenesis of this disease. Current research and drug targets in diabetes have hitherto focused on atherosclerosis, but vascular calcification is now recognised as an independent predictor of cardiovascular morbidity and mortality. An emerging regulatory pathway for vascular calcification in diabetes involves the receptor activator for nuclear factor κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG). Important novel biomarkers of calcification are related to levels of glycation and inflammation in diabetes. Several therapeutic strategies could have advantageous effects on the vasculature in patients with diabetes, including targeting the RANKL and receptor for AGE (RAGE) signalling pathways, since there has been little success-at least in macrovascular outcomes-with conventional glucose-lowering therapy. There is substantial and relevant clinical and basic science evidence to suggest that modulating RANKL-RANK-OPG signalling, RAGE signalling and the associated proinflammatory milieu alters the natural course of cardiovascular complications and outcomes in people with diabetes. However, further research is critically needed to understand the precise mechanisms underpinning these pathways, in order to translate the anti-calcification strategies into patient benefit.

Prevalence of polymorphisms in OPG, RANKL and RANK as potential markers for Charcot arthropathy development

“…Although CN develops as a consequence of neuropathy, presence of inflammation and abnormal bone deformation indicate that additional factors are responsible for its occurrence. Details of pathogenesis of CN are still unknown but the available data indicate that there is a strong link between OPG/RANKL/RANK axis and this disease 8, 9 .…”

“…processes that are likely impaired in CN 7 . Moreover, altered levels of RANKL and OPG have been linked to the development of vascular calcification, which has been proposed as one of the causes of this disease 9, 14 . A recent study indicated that the observed bone destruction in CN could be partially caused by an increase in the RANKL gene expression and subsequent local inflammation in the affected limb 15 .…”

“…A recent study indicated that the observed bone destruction in CN could be partially caused by an increase in the RANKL gene expression and subsequent local inflammation in the affected limb 15 . It has been also proposed that an increased bone resorption and calcification of blood vessels could lead to the development of Charcot arthropathy or intensify the development of this disease 9, 15, 16 . Therefore, increased RANKL/OPG ratio can be both, a symptom and a cause in the development of the Charcot arthropathy.…”

Prevalence and correlates of mitral annular calcification in adults with chronic kidney disease: Results from CRIC study

“…Mechanisms related to other risk factors, such as obesity and body mass index (BMI), low HDL <40, diabetes mellitus, and female gender, may be too far upstream or insufficient in severity. These include inflammatory markers (IL-1, IL-6, TNFα or adipocytokines specific to fatty tissue) [18]; the nuclear factor kβ ligand (RANKL) - receptor activator and nuclear factor kβ (RANK) - osteoprotegerin (OPG) signaling pathway [25–27] inducing osteoclastogenesis [28–34]; cholesterol reducing and anti-inflammatory benefits of HDL [35, 36]. Also, we know that the benefits of lipid lowering medications decrease with advancing kidney disease [37].…”

The effects of insulin and liraglutide on osteoprotegerin and vascular calcification in vitro and in patients with type 2 diabetes

“…Furthermore, the administration of OPG has been shown to decrease VC in atherogenic mice and to prevent vitamin D-induced VC in rodent models (17,18). The precise mechanism by which OPG exerts these effects is the subject of ongoing debate, but recent findings have suggested that its inhibitory effects on VC may be mediated by the ability of OPG to block the actions of receptor activator of nuclear factor kappa-b ligand (RANKL), another protein that has been identified within the vascular wall and one that has been reported to induce osteoblastic behaviour in VSMCs (19). Thus, the significant insulin-induced downregulation of OPG reported in the present paper may lead to unopposed RANKL activity, which gives rise to a proosteoblastic phenotype within the vasculature.…”