Response to Letter to the Editor: “Advanced Glycation End Products and esRAGE Are Associated With Bone Turnover and Incidence of Hip Fracture in Older Men” Free

We want to clarify that the assay used in our publication was that for human soluble receptor for advanced glycation end products (sRAGE) from R&D Systems, which measures both types of circulating sRAGE in the circulation, namely that derived from cell surface cleavage of receptor for advanced glycation end products (RAGE) and endogenous secretory RAGE (esRAGE). Although we originally stated that we measured esRAGE, this change does not alter our findings, which demonstrate that after adjustment for potential confounders, sRAGE was inversely associated with fasting glucose and positively associated with bone formation (1). Circulating sRAGE was similar in men with and without diabetes (1).

Both relatively low and high levels of circulating sRAGE and esRAGE have been associated with a range of different disease states. Low circulating sRAGE concentrations have been associated with coronary heart disease and atherosclerosis, and low esRAGE has been associated with heart failure (2–4). It has been reported that in people with diabetes, circulating sRAGE is both low (5) and high (6, 7), although low circulating esRAGE concentrations have also been reported (8, 9). High levels of sRAGE and esRAGE have been associated with coronary heart disease events in patients with type 2 diabetes (10). Additionally, and as Dr. Asadipooya notes, proteolytic cleavage of RAGE via matrix metalloproteinases is a source of sRAGE, and thus sRAGE production may be increased in diabetes owing to increased expression of matrix metalloproteinases (11). Interpretation of changes in circulating sRAGE and esRAGE is thus dependent on the pathophysiological context.

Both components of sRAGE (cleaved RAGE and esRAGE) may act as decoy receptors for RAGE ligands such as advanced glycation end products (AGEs) and compete with RAGE for ligand binding (11, 12), reducing the effect of the AGE/RAGE interaction. As we have demonstrated that sRAGE is positively associated with bone formation markers, we postulated that sRAGE may reduce deleterious effects of AGEs in bone via its action as a decoy receptor. We agree with Dr. Asadipooya that elevated sRAGE may also be a marker for AGE/RAGE production or destruction, from immune and other cells. Thus, an alternative interpretation for our findings would be that activity of the AGE/RAGE pathway is associated with bone turnover in older men, with sRAGE representing a biomarker rather than a mediating factor.

Abbreviations:

Abbreviations:
 
• AGE

  advanced glycation end product

 
• esRAGE

  endogenous secretory receptor for advanced glycation end products

 
• RAGE

  receptor for advanced glycation end products

 
• sRAGE

  soluble receptor for advanced glycation end products.

Acknowledgments

Disclosure Summary: The authors have nothing to disclose.

References