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(American Journal of Pathology. 2006;169:2236-2244.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060398

An Increased Osteoprotegerin Serum Release Characterizes the Early Onset of Diabetes Mellitus and May Contribute to Endothelial Cell Dysfunction

Paola Secchiero^*, Federica Corallini^*, Assunta Pandolfi, Agostino Consoli, Riccardo Candido, Bruno Fabris, Claudio Celeghini^¶, Silvano Capitani^* and Giorgio Zauli^¶

From the Department of Morphology and Embryology,^* University of Ferrara, Ferrara, Italy; Aging Research Center, Aging Research Center,"G. D’Annunzio" University Foundation, Chieti-Pescara, Italy; Diabetic Center, Trieste, Italy; and the Departments of Clinical Medicine and Neurology, and Human Normal Morphology,^¶ University of Trieste, Trieste, Italy

Serum osteoprotegerin (OPG) is significantly increased in diabetic patients, prompting expanded investigation of the correlation between OPG production/release and glycemic levels. Serum levels of OPG, but not of its cognate ligand receptor activator of nuclear factor-B ligand (RANKL), were significantly increased in type 2 diabetes mellitus patients compared with healthy blood donors. Serum OPG was also significantly elevated in a subgroup of recently diagnosed diabetic patients (within 2 years). The relationship between serum OPG and diabetes mellitus onset was next investigated in apoE-null and littermate mice. Serum OPG increased early after diabetes induction in both mouse strains and showed a positive correlation with blood glucose levels and an inverse correlation with the levels of free (OPG-unbound) RANKL. The in vitro addition of tumor necrosis factor- to human vascular endothelial cells, but not human peripheral blood mononuclear cells, markedly enhanced OPG release in culture. In contrast, high glucose concentrations did not modulate OPG release when used alone or in association with tumor necrosis factor-. Moreover, the ability of soluble RANKL to activate the extracellular signal-regulated kinase/mitogen-activated protein kinase and endothelial nitric-oxide synthase pathways in endothelial cells was neutralized by preincubation with recombinant OPG. Altogether, these findings suggest that increased OPG production represents an early event in the natural history of diabetes mellitus, possibly contributing to disease-associated endothelial cell dysfunction.

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