The RANKL/RANK/OPG signaling pathway mediates medial arterial calcification in diabetic charcot neuroarthropathy

Agbor Ndip, Alfred Williams, Edward B. Jude, Ferdinand Serracino-Inglott, Steve Richardson, J. V. Smyth, Andrew J M Boulton, M. Yvonne Alexander

    Research output: Contribution to journalArticlepeer-review

    Abstract

    OBJECTIVE - The receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) signaling pathway (RANKL/RANK/OPG signaling) is implicated in the osteolysis associated with diabetic Charcot neuroarthropathy (CN); however, the links with medial arterial calcification (MAC) seen in people with CN are unclear. This study aimed to investigate the role of RANKL/OPG in MAC in patients with CN. RESEARCH DESIGN AND METHODS - Enzyme-linked immunosorbent assay and Bio-plex multiarray technology were used to quantify a range of cytokines, including RANKL and OPG in sera from 10 patients with diabetes, 12 patients with CN, and 5 healthy volunteers. Human tibial artery segments were immunohistochemically stained with Alizarin red and human RANKL antibody. Human vascular smooth muscle cells (VSMCs) were also explanted from arterial segments for in vitro studies. RESULTS - We demonstrate colocalization and upregulation of RANKL expression in areas displaying MAC. Systemic levels of RANKL, OPG, and inflammatory cytokines (interleukin-8, granulocyte colony-stimulating factor) were elevated in those with CN compared with diabetic patients and healthy control subjects. Human VSMCs cultured in CN serum showed accelerated osteoblastic differentiation (alkaline phosphatase activity) and mineralization (alizarin red staining) compared with cells treated with diabetic or control serum (P <0.05). Coincubation with OPG, the decoy receptor for RANKL, attenuated osteogenic differentiation of VSMCs and was independent of a high calcium-phosphate milieu. The accelerated mineralization induced by RANKL and CN serum correlated with nuclear translocation of nuclear factor-κB, a process abrogated by OPG. CONCLUSIONS - Our data provide direct evidence that RANKL/ RANK/OPG signaling is modulated in patients with CN and plays a role in vascular calcification. This study highlights this pathway as a potential target for intervention. © 2011 by the American Diabetes Association.
    Original languageEnglish
    Pages (from-to)2187-2196
    Number of pages9
    JournalDiabetes
    Volume60
    Issue number8
    DOIs
    Publication statusPublished - Aug 2011

    Fingerprint

    Dive into the research topics of 'The RANKL/RANK/OPG signaling pathway mediates medial arterial calcification in diabetic charcot neuroarthropathy'. Together they form a unique fingerprint.

    Cite this