RANKL–OPG and RAGE modulation in vascular calcification and diabetes: novel targets for therapy
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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.
KeywordsAGE Charcot neuroarthropathy Diabetes OPG RAGE RANKL Review Vascular calcification
Chronic kidney disease
Generalised arterial calcification of infancy
Receptor for AGE
Receptor activator for nuclear factor κB
Receptor activator for nuclear factor κB ligand
Vascular smooth muscle cell
We acknowledge support from the Manchester NIHR Biomedical Research Unit and Manchester Academic Health Science Centre (MAHSC).
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
All authors were responsible for the conception and design of the manuscript, drafting the article and revising it critically for important intellectual content. All authors approved the version to be published.
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