, Volume 57, Issue 11, pp 2251–2260 | Cite as

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

  • Agbor NdipEmail author
  • Fiona L. Wilkinson
  • Edward B. Jude
  • Andrew J. M. Boulton
  • M. Yvonne Alexander


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.


AGE 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.

Contribution statement

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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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Agbor Ndip
    • 1
    • 2
    • 3
    • 4
    Email author
  • Fiona L. Wilkinson
    • 5
  • Edward B. Jude
    • 3
    • 6
  • Andrew J. M. Boulton
    • 1
    • 3
    • 7
  • M. Yvonne Alexander
    • 5
    • 7
  1. 1.Department of Medicine and DiabetesManchester Royal InfirmaryManchesterUK
  2. 2.Department of Diabetes and EndocrinologyWarrington and Halton NHS TrustWarringtonUK
  3. 3.Centre for Endocrinology and Diabetes, Faculty of Medical and Human SciencesUniversity of ManchesterManchesterUK
  4. 4.Manchester Diabetes CentreManchesterUK
  5. 5.Healthcare Science Research InstituteManchester Metropolitan UniversityManchesterUK
  6. 6.Department of Diabetes, Diabetes CentreTameside General HospitalAshton-Under-LyneUK
  7. 7.Manchester Academic Health Science CentreManchesterUK

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