REVIEW RANKL–OPG and RAGE modulation in vascular calcification and diabetes: novel targets for therapy Agbor Ndip & Fiona L. Wilkinson & Edward B. Jude & Andrew J. M. Boulton & M. Yvonne Alexander Received: 1 April 2014 /Accepted: 17 July 2014 /Published online: 12 August 2014 # Springer-Verlag Berlin Heidelberg 2014 Abstract Type 2 diabetes is associated with increased cardio- vascular morbidity and mortality and early vascular ageing. This takes the form of atherosclerosis, with progressive vas- cular calcification being a major complication in the patho- genesis 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 regula- tory 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 con- ventional glucose-lowering therapy. There is substantial and relevant clinical and basic science evidence to suggest that modulating RANKL–RANK–OPG signalling, RAGE signal- ling 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. Keywords AGE . Charcot neuroarthropathy . Diabetes . OPG . RAGE . RANKL . Review . Vascular calcification Abbreviations CKD Chronic kidney disease GACI Generalised arterial calcification of infancy OPG Osteoprotegerin RAGE Receptor for AGE RANK Receptor activator for nuclear factor κB RANKL Receptor activator for nuclear factor κB ligand VSMC Vascular smooth muscle cell Historical perspective of vascular calcification The earliest recognition of vascular calcification was made in a 5,300 year-old naturally mummified iceman discovered in 1991 in the Tyrolean Alps on the Austrian–Italian border, where radiological evidence showed the presence of aortic and carotid calcification. Vascular calcification was also Agbor Ndip and Fiona L. Wilkinson are joint first authors. A. Ndip : A. J. M. Boulton Department of Medicine and Diabetes, Manchester Royal Infirmary, Manchester, UK A. Ndip Department of Diabetes and Endocrinology, Warrington and Halton NHS Trust, Warrington, UK A. Ndip : E. B. Jude : A. J. M. Boulton Centre for Endocrinology and Diabetes, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK A. Ndip (*) Manchester Diabetes Centre, 193, Hathersage Road, Manchester M13 0JE, UK e-mail: agbor.ako@manchester.ac.uk F. L. Wilkinson : M. Y. Alexander Healthcare Science Research Institute, Manchester Metropolitan University, Manchester, UK E. B. Jude Department of Diabetes, Diabetes Centre, Tameside General Hospital, Ashton-Under-Lyne, UK A. J. M. Boulton : M. Y. Alexander Manchester Academic Health Science Centre, Manchester, UK Diabetologia (2014) 57:2251–2260 DOI 10.1007/s00125-014-3348-z