Diabetologia

, Volume 57, Issue 11, pp 2251–2260

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
Review

DOI: 10.1007/s00125-014-3348-z

Cite this article as:
Ndip, A., Wilkinson, F.L., Jude, E.B. et al. Diabetologia (2014) 57: 2251. doi:10.1007/s00125-014-3348-z

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.

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

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Agbor Ndip
    • 1
    • 2
    • 3
    • 4
  • 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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