title: An increased osteoprotegerin serum release characterizes the early onset of diabetes mellitus and may contribute to endothelial cell dysfunction.
abstract: 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-kappaB 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-alpha 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-alpha. 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.
authors.affiliation: Department of Morphology and Embryology, University of Ferrara, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Secchiero
authors.forename: Federica
authors.initials: F
authors.lastname: Corallini
authors.forename: Assunta
authors.initials: A
authors.lastname: Pandolfi
authors.forename: Agostino
authors.initials: A
authors.lastname: Consoli
authors.forename: Riccardo
authors.initials: R
authors.lastname: Candido
authors.forename: Bruno
authors.initials: B
authors.lastname: Fabris
authors.forename: Claudio
authors.initials: C
authors.lastname: Celeghini
authors.forename: Silvano
authors.initials: S
authors.lastname: Capitani
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zauli
mesh_terms: D000368:Aged; D000818:Animals; D001011:Aorta; D001057:Apolipoproteins E / Q000235:genetics; D001786:Blood Glucose / Q000502:physiology; D016207:Cytokines / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D053244:Osteoprotegerin / Q000097:blood*; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D001057:Apolipoproteins E; D001786:Blood Glucose; D016207:Cytokines; D053244:Osteoprotegerin; D053245:RANK Ligand; D005947:Glucose